Method and medicine for promoting pathological TDP-43 protein degradation

Abstract

The invention relates to a method for promoting pathological TDP-43 protein degradation. Comprising the step of administering a therapeutically effective amount of one or more compounds selected from the group consisting of a component of a plasminogen activation pathway and a compound capable of directly activating plasminogen or indirectly activating plasminogen by activating an upstream component of the plasminogen activation pathway to a subject, the invention relates to a compound capable of simulating the activity of plasminogen or fibrinolysin, a compound capable of up-regulating the expression of plasminogen or a plasminogen activator, a plasminogen analogue, a fibrinolysin analogue, a tPA or uPA analogue and an antagonist of a fibrinolytic inhibitor. The invention further relates to a medicine for promoting degradation of the pathological TDP-43 protein and application of the medicine.

Description

A method and drug for promoting degradation of pathological TDP-43 protein Technical Field The present application relates to a method for promoting the degradation of pathological TDP-43 protein and treating a disease related to pathological TDP-43 protein, comprising administering an effective amount of a plasminogen activation pathway-related compound such as plasminogen or plasmin to a subject. The present application also relates to a pharmaceutical composition containing a plasminogen activation pathway-related compound such as plasminogen or plasmin for this purpose. Background Art TDP-43, the full name of which is Transactive response DNA-binding protein 43, is a protein widely present in cells. It can bind to DNA and RNA, and plays an important role in RNA transcription, alternative splicing, and mRNA stability regulation in cells. Normal TDP-43 is located in various subcellular structures, including mitochondria, mitochondrial-associated membranes, RNA granules, and stress granules, to regulate endoplasmic reticulum-mitochondria binding, mitochondrial protein translation, and mRNA transport and translation. Therefore, the normal physiological function of TDP-43 is particularly important for cell survival. TDP-43 can also bind proteins to each other to form homodimers and polymers. There is a glutamine-rich region at the C-terminus of TDP-43, which is responsible for most of the aggregation. Recent studies have found that several factors affect the aggregation process of TDP-43, which either change the protein structure itself or change the proteins in the surrounding environment, thereby causing TDP-43 aggregation. TDP-43 aggregates have been identified in an increasing number of neurodegenerative disorders (Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64), including but not limited to: frontotemporal dementia (sporadic or familial, with or without motor neuron disease (MND), with progranulin (GRN) mutation, with TARDBP mutation, with valosine-containing protein (VCP) mutation, linked to chromosome 9p, corticobasal degeneration, frontotemporal degeneration with ubiquitin-positive inclusions, Argyrophilic grain disease, Pick's disease, etc.), amyotrophic lateral sclerosis (sporadic ALS, with TARDBP mutation, with angiogenin (ANG) mutation), Alzheimer's disease (AD, sporadic and familial), Down syndrome (Down syndrome), and other neurodegenerative diseases. syndrome), Familial British dementia, polyglutamine diseases (Huntington's disease and spinocerebellar ataxia type 3 (SCA3; also known as Machado-Joseph Disease)), hippocampal sclerosis dementia, and myopathies (sporadic inclusion body myositis; inclusion body myopathy with mutations in valosin-containing protein (VCP); and Paget disease of bone and frontotemporal dementia); oculopharyngeal muscular dystrophy with rimmed vacuoles; and myofibrillar myopathy with mutations in the sarcomere protein (MYOT) gene or mutations in the gene encoding desmin (DES). Aggregated TDP-43 from patient brains shows a large number of abnormal modifications, including hyperphosphorylation, ubiquitination, acetylation, and C-terminal fragments cleaved by proteolysis (Arai et al., Biochemical and Biophysical Research Communications 351 (2006) 602-611; Neumann et al., Science 314, (2006), 130-133; Neumann et al., Acta Neuropathol. (2009) 117: 137-149; Hasegawa et al., (2008) Annals of Neurology Vol 64 No 1, 60-70; Cohen et al., Nat Commun. 6: 5845, 2015). Another characteristic feature of TDP-43 pathological conditions is the redistribution and accumulation of TDP-43 from the nucleus to the cytoplasm. The hallmark lesions of FTLD-TDP are neuronal cytoplasmic inclusions and glial cytoplasmic inclusions (NCI (neuronal cytoplasmic inclusion) and GCI (glial cytoplasmic inclusion) respectively) and dystrophic neurites (DN). Frontotemporal dementia (FTD) is a clinical term that covers a broad spectrum of disorders characterized by pathological features based on degeneration of the frontal and temporal lobes, called frontotemporal lobar degeneration (FTLD). FTD is the second most common cause of early degenerative dementia in the age group under 65 years old (Le Ber, Revue Neurologique 169 (2013) 811-819). FTD manifests as several syndromes, including bvFTD characterized by personality and behavioral changes; semantic dementia (SD) and progressive nonfluent aphasia (PNFA) characterized by changes in language function; corticobasal syndrome (CBS), progressive supranuclear palsy syndrome and motor neuron disease (FTD-MND) characterized by motor dysfunction. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature loss of upper and lower motor neurons. The progression of ALS is characterized by fatal paralysis and respiratory failure, with a course of 1 to 5 years from diagnosis to death. In most cases of sporadic ALS, the neuropathology is characterized by abnormal cytoplasmic accumulation of TDP-43 in neurons and glial cells of the primary motor cortex, brainstem motor nuclei, spinal cord, and associated white matter tracts. ALS with dementia involves accumulation of TDP-43 in the extramotor neocortex and hippocampus. The role of TDP-43 phosphorylation in ALS patients has been studied with the aid of antibodies. Exploration has been conducted (Hasegawa et al., Ann Neurol 2008; 64: 60-70; Neumannet al., Acta Neuropathol (2009) 117: 137-149). TDP-43 pathology occurs in the brains of up to 57% of patients with Alzheimer's disease (Josephs KA et al., Acta Neuropathol. 2014; 127(6): 811-824; Josephs KA et al., Acta Neuropathol. 2014; 127(3): 441-450; McAleese et al., Brain Pathol. 2017 Jul; 27(4): 472-479). TDP-43 aggregation is associated with the patient's age and is associated with cognitive decline, memory loss, and medial temporal atrophy in AD. TDP-43-positive patients are 10 times more likely to die with cognitive impairment than TDP-43-negative subjects. Pathological TDP-43 follows a general progressive deposition pattern, with TDP-43 first deposited in the amygdala (stage I), then in the hippocampus, limbic, temporal, and finally frontostriatum (stage V) (Josephs KA et al., Acta Neuropathol. 2014; 127(6):811-824; Josephs KA et al., Acta Neuropathol. 2014; 127(3):441-450). Recent evidence supports the concept that amyloid-β, tau, α-synuclein, and TDP-43 spread proteolytically in neuronal tissue via a prion-like mechanism (Hasegawa et al., 2017). Although ALS onset and initial symptoms vary significantly between patients, a common feature of disease progression is the spread of pathology from the initial focal area to most neurons. The continued worsening of symptoms can be explained by this progressive spread of TDP-43 pathology. TDP-43 pathology in the brains of ALS patients has been shown to spread in a four-stage process and is thought to spread transsynaptically via axonal projections from the cortex using anterograde axonal transport (Brettschneider et al., Ann Neurol. 2013 July; 74(1): 20-38.). Some recent reports involve the spread of TDP-43 at the molecular level in a variety of in vitro models. Insoluble TDP-43 preparations from patient brains are able to induce intracellular aggregate formation in vitro (Nonaka et al., Cell Reports 4 (2013), 124-134; Feiler et al., 2015; Porta et al., Nat. Comm., 2018). Moreover, it has recently been shown that patient-derived pathological TDP-43 can lead to extensive deposition of endogenous TDP-43 after inoculation into transgenic and wild-type mice (Porta et al., Nat. Comm., 2018). In addition, it has been shown that intracellular TDP-43 aggregates are released in conjunction with exosomes before spreading to the next cell (Nonaka et al., Cell Reports 4 (2013, 124-134)). TDP-43 aggregation and pathological spread are the main hallmarks of ALS and FTD, currently incurable and fatal diseases. Mutations in TDP-43 are associated with familial cases of ALS and FTD, providing a causal link between TDP-43 misfolding and disease progression. Therefore, there is a need to find methods that promote degradation of pathological TDP-43 protein or reduce TDP-43 aggregates to treat diseases associated with pathological TDP-43 protein. SUMMARY OF THE INVENTION The present application study found that plasminogen can promote the degradation of pathological TDP-43 protein in nerve and muscle tissues to some extent, and treat diseases associated with pathological TDP-43 protein aggregation, such as ALS and frontotemporal dementia (also known as frontotemporal dementia). Specifically, this application relates to the following: 1. A method for promoting degradation of pathological TDP-43 protein, comprising administering to a subject a therapeutically effective amount of one or more compounds selected from the following: components of the plasminogen activation pathway, compounds that can directly activate plasminogen or indirectly activate plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors. 2. The method of claim 1, wherein the components of the plasminogen activation pathway are selected from plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogs containing one or more kringle domains and protease domains of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activator, tPA and uPA. 3. The method of item 1, wherein the antagonist of the fibrinolytic inhibitor is an inhibitor of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin, such as an antibody. 4. The method of any one of items 1-3, wherein the compound has one or more of the following activities: promoting the degradation of pathological TDP-43 proteins in neural tissue, promoting the degradation of pathological TDP-43 proteins in muscle tissue. In some embodiments, the compound promotes the degradation of pathological TDP-43 proteins in and / or outside muscle tissue cells. In some embodiments, the compound promotes the degradation of pathological TDP-43 proteins in and / or outside neural tissue cells (e.g., nerve cells or glial cells). 5. A method for treating a pathological TDP-43 protein-related disease in a subject, comprising administering to the subject a therapeutically effective amount of one or more compounds selected from the following: components of the plasminogen activation pathway, proteins that can directly activate plasminogen or activate plasminogen activator The invention relates to a compound that indirectly activates plasminogen by activating an upstream component of the plasminogen pathway, a compound that simulates the activity of plasminogen or plasmin, a compound that can upregulate the expression of plasminogen or plasminogen activator, a plasminogen analog, a plasmin analog, a tPA or uPA analog, and an antagonist of a fibrinolytic inhibitor, wherein the pathological TDP-43 protein-related disease is one or more selected from the following: amyotrophic lateral sclerosis (ALS), bulbar amyotrophic lateral sclerosis, Fus gene mutation amyotrophic lateral sclerosis, Alzheimer's disease, argyrophilic grain disease, ALS-parkinsonism dementia complex of Guam, vascular dementia, frontotemporal dementia, semantic dementia, and so on. dementia, dementia with Lewy bodies, Huntington's disease, Spinocere bellarataxia, inclusion body myopathy, inclusion body myositis, and Parkinson's disease. 6. The method of claim 5, wherein the components of the plasminogen activation pathway are selected from plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogs containing one or more kringle domains and protease domains of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activator, tPA and uPA. 7. The method of item 5, wherein the antagonist of the fibrinolytic inhibitor is an inhibitor of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin, such as an antibody. 8. The method of any one of items 1 to 7, wherein the compound is plasminogen or plasmin. 9. The method of any one of items 1-8, wherein the plasminogen is Glu-plasminogen, Lys-plasminogen, or a conservatively substituted variant thereof. 10. The method of any one of items 1-9, wherein the plasminogen has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with sequence 2 and has lysine binding activity and / or proteolytic activity of plasminogen. 11. The method of any one of items 1 to 10, wherein the plasminogen comprises one or more selected from the group consisting of: 1) having a serine protease domain as shown in SEQ ID NO:14; 2) a serine protease domain that is at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 14 and retains proteolytic activity; 3) a Kringle domain selected from one or more of Kringle 1, Kringle 2, Kringle 3, Kringle 4 and Kringle 5; and 4) A Kringle domain that is at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identical to one or more of Kringle 1, Kringle 2, Kringle 3, Kringle 4, and Kringle 5 and that retains lysine binding activity. 12. The method according to any one of items 1 to 11, wherein the plasminogen is selected from Glu-plasminogen, Lys-plasminogen, mini-plasminogen, micro-plasminogen, delta-plasminogen or variants thereof that retain the proteolytic activity of plasminogen. 13. The method according to any one of items 1 to 12, wherein the plasminogen comprises the amino acid sequence shown in sequence 2, 6, 8, 10, or 12, or comprises a conservatively substituted variant of the amino acid sequence shown in sequence 2, 6, 8, 10, or 12. 14. The method of any one of items 1-13, wherein the plasminogen is used in combination with one or more other treatment methods or drugs. 15. The method of claim 14, wherein the other treatment methods include cell therapy (including stem cell therapy), supportive therapy and physical therapy. 16. The method of any one of items 1-15, wherein the plasminogen is administered by nasal inhalation, nebulized inhalation, nasal drops, eye drops, ear drops, intravenous, intraperitoneal, subcutaneous, intracranial, intrathecal, intraarterial or intramuscular administration. In some specific embodiments, the plasminogen pathway activator is administered in combination with one or more other drugs and / or treatment methods, preferably, the treatment method includes cell therapy (e.g., stem cell therapy) and gene therapy, such as antisense RNA, small molecule splicing modifiers. In some specific embodiments, the plasminogen pathway activator is a component of the plasminogen activation pathway, such as plasminogen. In some specific embodiments, the plasminogen comprises or has an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in sequence 2, 6, 8, 10 or 12, and has plasminogen activity and / or lysine binding activity. In some embodiments, the plasminogen is based on sequence 2, 6, 8, 10 or 12, with additions, deletions and / or substitutions of 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1- 20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acid, and a protein with plasminogen activity and / or lysine binding activity. In some specific embodiments, the plasminogen activity is the proteolytic activity of plasminogen. In some specific embodiments, the plasminogen is a protein comprising a plasminogen active fragment and having plasminogen activity and / or lysine binding activity. In some specific embodiments, the plasminogen activity is the proteolytic activity of plasminogen. In some specific embodiments, the plasminogen activity is the proteolytic activity of plasminogen. In some specific embodiments, the plasminogen active fragment comprises or has a plasminogen serine protease domain or a plasminogen protease domain. In some specific embodiments, the amino acid sequence of the plasminogen active fragment is as shown in Sequence 14. In some specific embodiments, the plasminogen is selected from Glu-plasminogen (human full-length plasminogen), Lys-plasminogen (human full-length plasminogen after cleavage between amino acids 76-77), mini-plasminogen (comprising Kringle 5 (K5) and a serine protease domain), micro-plasminogen (comprising a serine protease domain), delta-plasminogen (comprising Kringle 1 and a serine protease domain), or variants thereof that retain plasminogen activity. In some specific embodiments, the plasminogen is human full-length plasminogen, or a variant or fragment thereof that still retains plasminogen activity and / or lysine binding activity. In some embodiments, the plasminogen is a human plasminogen ortholog from a primate or rodent, or a variant or fragment thereof that still retains plasminogen activity and / or lysine binding activity. In some embodiments, the plasminogen comprises an amino acid sequence as shown in SEQ ID NOs: 2, 6, 8, 10, or 12. In some embodiments, the plasminogen is human native plasminogen. In some specific embodiments, the plasminogen pathway activator is administered systemically or locally, for example, by intravenous, intramuscular, nasal inhalation, nebulized inhalation, or nasal drops. In some embodiments, the subject is a human. In some embodiments, the subject lacks or is deficient in plasminogen. In some embodiments, the deficiency or deficiency is congenital, secondary, and / or local. In some embodiments, the plasminogen is administered at 0.0001-2000 mg / kg, 0.001-800 mg / kg, 0.01-600 mg / kg, 0.1-400 mg / kg, 1-200 mg / kg, 1-100 mg / kg, 10-100 mg / kg (calculated per kilogram of body weight) or 0.0001-2000 mg / cm per day. 2 , 0.001-800mg / cm 2 , 0.01-600mg / cm 2 , 0.1-400mg / cm2 , 1-200mg / cm 2 , 1-100mg / cm 2 10-100mg / cm 2 The dosage is calculated per square centimeter of body surface area and is administered every day, every two days or every three days. On the one hand, the present application also relates to a pharmaceutical composition, a drug, a preparation, a kit, and a product for use in the above method, comprising the above-mentioned plasminogen pathway activator, such as the above-mentioned plasminogen. In some embodiments, the pharmaceutical composition, drug, preparation comprises a pharmaceutically acceptable carrier and a plasminogen pathway activator, such as a component of the plasminogen activation pathway, such as plasminogen. In some embodiments, the kit and article comprise one or more containers, wherein the container comprises the pharmaceutical composition, drug or preparation. In some embodiments, the kit or article further comprises a label or instructions for use, which indicates the use of a plasminogen pathway activator, such as a component of the plasminogen activation pathway, such as plasminogen for the above method. In some embodiments, the kit or article further comprises one or more additional containers, wherein the container contains one or more other drugs. In one aspect, the present application also relates to a plasminogen pathway activator for the above-mentioned use, such as the plasminogen described above. On the one hand, the present application also relates to the use of a therapeutically effective amount of the above-mentioned plasminogen pathway activator in the preparation of a pharmaceutical composition, a drug, a preparation, a kit, or a product for the above-mentioned method. In some embodiments, the plasminogen pathway activator is selected from one or more of the following: components of the plasminogen activation pathway, compounds that can directly activate plasminogen or indirectly activate plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors. In some specific embodiments, the component of the plasminogen activation pathway is selected from plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogs containing one or more kringle domains and a protease domain of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activator, tPA and uPA. In some specific embodiments, the antagonist of the fibrinolysis inhibitor is an antagonist of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin, such as an antibody to PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin. In some specific embodiments, the plasminogen pathway activator is administered in combination with one or more other drugs and / or treatments, preferably, the treatments include cell therapy (e.g., stem cell therapy) and gene therapy, such as antisense RNA, small molecule splicing modifiers. In some embodiments, the plasminogen pathway activator is plasminogen Activation pathway components, such as plasminogen. In some specific embodiments, the plasminogen comprises or has an amino acid sequence with at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in sequence 2, 6, 8, 10 or 12, and has plasminogen activity and / or lysine binding activity. In some embodiments, the plasminogen is a protein that adds, deletes and / or replaces 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acids on the basis of sequence 2, 6, 8, 10 or 12, and has plasminogen activity and / or lysine binding activity. In some specific embodiments, the plasminogen activity is the proteolytic activity of plasminogen. In some specific embodiments, the plasminogen is a protein comprising a plasminogen active fragment and having plasminogen activity and / or lysine binding activity. In some specific embodiments, the plasminogen activity is the proteolytic activity of plasminogen. In some specific embodiments, the plasminogen active fragment comprises or has a plasminogen serine protease domain or a plasminogen protease domain. In some specific embodiments, the amino acid sequence of the plasminogen active fragment is as shown in Sequence 14. In some specific embodiments, the plasminogen is selected from Glu-plasminogen (human full-length plasminogen), Lys-plasminogen (human full-length plasminogen after cleavage between amino acids 76-77), mini-plasminogen (comprising Kringle 5 (K5) and a serine protease domain), micro-plasminogen (comprising a serine protease domain), delta-plasminogen (comprising Kringle 1 and a serine protease domain), or variants thereof that retain plasminogen activity. In some specific embodiments, the plasminogen is human full-length plasminogen, or a variant or fragment thereof that still retains plasminogen activity and / or lysine binding activity. In some embodiments, the plasminogen is a human plasminogen ortholog from a primate or rodent, or a variant or fragment thereof that still retains plasminogen activity and / or lysine binding activity. In some embodiments, the plasminogen comprises an amino acid sequence as shown in SEQ ID NOs: 2, 6, 8, 10, or 12. In some embodiments, the plasminogen is human native plasminogen. In some embodiments, the plasminogen pathway activator, e.g., a component of the plasminogen activation pathway, e.g., plasminogen, is administered in combination with one or more other drugs and / or treatments. In some embodiments, the plasminogen pathway activator, e.g., a component of the plasminogen activation pathway, e.g., plasminogen, is administered intravenously, intramuscularly, intrathecally, by nasal inhalation, by nebulization inhalation, by nose drops, or by eye drops. In some embodiments, the pharmaceutical composition, medicament, or formulation comprises a pharmaceutically acceptable carrier and a plasminogen pathway activator, such as a component of the plasminogen activation pathway, such as a fibrinolytic In some embodiments, the kits and articles of manufacture comprise one or more containers containing the pharmaceutical composition, medicament or formulation. In some embodiments, the kits or articles of manufacture further comprise a label or instructions for use, which indicates the use of a plasminogen pathway activator, such as a component of a plasminogen activation pathway, such as plasminogen, for the above-mentioned purposes. In some embodiments, the kit or article of manufacture further comprises one or more additional containers containing one or more other drugs. The present invention explicitly covers all combinations of technical features belonging to the embodiments of the present invention, and the technical solutions after such combinations have been explicitly disclosed in this application, just as the above technical solutions have been individually and explicitly disclosed. In addition, the present invention also explicitly covers the combination between the various embodiments and their elements, and the technical solutions after such combinations are explicitly disclosed in this article. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Schematic diagram of the mechanism by which plasminogen promotes pathological protein degradation in the central nervous system. Blood-brain barrier, basement membrane, endothelial cells, plasminogen (Plg), plasminogen receptor (PlgR), tissue-type plasminogen activator (tPA), conformationally abnormal proteins (CAP), plasmin (Plm), plasmin generated protein fragments (PGPFs), plasmin degradation products (PDP), lysosome, ubiquitin (UBI), ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), ubiquitin ligase (E3), proteasome, microglia, and nucleus. Existing results show that plasminogen can promote the degradation of central nervous system pathological proteins such as TDP-43 and superoxide dismutase-1 (SOD1), and can improve the clinical symptoms of various neurodegenerative diseases including amyotrophic lateral sclerosis. Based on the existing data, it is speculated that the mechanism by which plasminogen promotes the degradation of central nervous system pathological proteins is as follows: (1) Plasminogen crosses the blood-brain barrier, enters the central nervous system, and is enriched there, activated to form plasmin, which directly degrades central nervous system pathological proteins abnormally deposited in the extracellular matrix, such as amyloid protein Aβ. The degraded protein fragments are further phagocytosed by microglia and then degraded by lysosomes; (2) Plasminogen enters the cell or the nucleus through endocytosis, and is activated to form plasmin, which promotes the degradation of central nervous system pathological proteins such as TDP-43, SOD1, TAU, α-synuclein, etc.; (3) Plasminogen enters the cell to regulate the intracellular protein degradation system - the ubiquitin proteasome system (ubiquitin proteasome (4) Plasminogen enters the cell to regulate the function of the intracellular protein degradation system - the autophagy-lysosome system, and degrades the central nervous system pathological proteins through the autophagy-lysosome system; (5) In addition, some studies have reported that central nervous system pathological proteins including TDP-43 and SOD1 have similar infectivity to prions, and plasminogen may have the ability to prevent central nervous system pathological proteins from spreading between cells. Figure 2A-B shows the effect of plasminogen on TDP-43 protein in normal mouse brain homogenate. A is a Western blot image, and B is the result of quantitative analysis of the optical density of the TDP-43 protein band. The results showed that the molecular weight of the recombinant TDP-43 protein monomer was about 43 kDa, the molecular weight of the high molecular weight TDP-43 protein (HMW) was >55 kDa, and the molecular weight of the low molecular weight TDP-43 fragment (LMW) was <40 kDa. In addition, in the normal mouse brain homogenate, the amount of TDP-43 monomer, HMW and LMW in the plasminogen group was significantly lower than that in the vehicle control group, and the difference was extremely significant (*** represents P <0.001, * represents P <0.05). This suggests that plasminogen can promote the cleavage of TDP-43 in normal mouse brain homogenate. Figure 3A-B shows the effect of plasminogen on TDP-43 protein in the brain homogenate of ALS model mice. A is a Western blot image, and B is the result of the quantitative analysis of the optical density of the TDP-43 protein band. The results showed that the molecular weight of the recombinant TDP-43 protein monomer was about 43 kDa, the molecular weight of the high molecular weight TDP-43 protein (HMW) was >55 kDa, and the molecular weight of the low molecular weight TDP-43 fragment (LMW) was <40 kDa. In addition, in the brain homogenate of ALS model mice, the amount of TDP-43 monomer, HMW and LMW in the plasminogen group was significantly lower than that in the vehicle control group, and the difference was extremely significant (*** represents P <0.001, ** represents P <0.01). This suggests that plasminogen can promote the cleavage of TDP-43 in the brain homogenate of ALS model mice. Figure 4A-B Plasminogen promotes TDP-43 protein degradation in spinal cord tissue of mice with amyotrophic lateral sclerosis model. A is a Western blot image, and B is the result of quantitative analysis of the optical density of TDP-43 protein bands. The results showed that the amount of TDP-43 monomer and low molecular weight TDP-43 in the spinal cord tissue of mice in the drug-treated group was significantly lower than that in the vehicle group, and the statistical difference was significant (* represents P<0.05). This shows that plasminogen can promote the degradation of TDP-43 in the spinal cord tissue of mice with amyotrophic lateral sclerosis model. Figure 5A-B Plasminogen promotes the degradation of TDP-43 protein in the brain tissue of ALS model mice injected with pathological TDP-43 protein. A is a Western blot image, and B is the result of quantitative analysis of the optical density of TDP-43 protein bands. The results showed that the amount of TDP-43 monomer and low molecular weight TDP-43 in the brain tissue of mice in the drug-treated group was significantly lower than that in the vehicle group, and the statistical difference was significant (* represents P<0.05). This shows that plasminogen can promote the degradation of TDP-43 in the brain tissue of ALS model mice. Figure 6A-I Representative images of immunofluorescence co-localization staining of plasminogen and TDP-43 in the spinal cord tissue of mice after administration of plasminogen to ALS model mice. AC: normal control group, DF: vehicle group, GI: drug administration group. The results showed that the positive staining of plasminogen (green fluorescence) in the spinal cord tissue of the drug administration group was significantly more than that of the vehicle group, indicating that the administered plasminogen can enter the spinal cord tissue and be enriched in the spinal cord tissue. In addition, plasminogen is present in the cytoplasm (as shown in △) and the nucleus (as shown in Plasminogen co-localizes with TDP-43 (red fluorescence) in the cytoplasm (▲) and in the nucleus ( The TDP-43 level in the spinal cord tissue of the drug-treated group was lower than that of the vehicle group, and the co-localization of plasminogen and TDP-43 in the drug-treated group was more than that in the vehicle group. This indicates that plasminogen can enter the spinal cord tissue and cells in the ALS model mice, co-localize with TDP-43, and degrade TDP-43. Figure 7A-I Representative images of immunofluorescence co-localization staining of plasminogen and TDP-43 in muscle tissue of mice after administration of plasminogen to ALS model mice. AC: normal control group, DF: vehicle group, GI: drug administration group. The results showed that the positive staining of plasminogen (green fluorescence) in muscle tissue of the drug administration group was significantly more than that of the vehicle group, indicating that plasminogen can be enriched in muscle tissue. In addition, plasminogen is present in the cytoplasm (as shown in △) and the nucleus (as shown in Plasminogen co-localizes with TDP-43 (red fluorescence) in the cytoplasm (▲) and in the nucleus ( This indicates that plasminogen can be enriched in muscle tissue, enter cells, and co-localize with TDP-43 in ALS model mice. Figure 8A-B shows the results of WB detection of TDP-43 levels in brain homogenates of mice with dementia induced by okadaic acid after administration of plasminogen. A is a Western blot image, and B is the result of quantitative analysis of the optical density of TDP-43 protein bands. The results showed that the levels of TDP-43 monomers and low molecular weight TDP-43 in the brain tissue of mice in the drug administration group were significantly lower than those in the vehicle group. This indicates that plasminogen can promote the degradation of TDP-43 in the brain tissue of mice with dementia induced by okadaic acid. Figure 9A-B shows the results of WB detection of TDP-43 levels in the renal nuclei of mice with amyotrophic sclerosis treated with plasminogen. A is a Western blot image, and B is the result of quantitative analysis of the optical density of the TDP-43 protein band. The results showed that the level of TDP-43 in the renal nuclei of the drug-treated group was significantly lower than that of the vehicle group (* represents P<0.05). This suggests that plasminogen can promote the degradation of TDP-43 in the renal nuclei. Figure 10A-D is the WB test results of TDP-43 levels in the cytoplasm and nucleus of NSC34 treated with plasminogen okadaic acid. A is the Western blot image of the cytoplasm, B is the quantitative analysis result of the optical density of the TDP-43 protein band in the cytoplasm, C is the Western blot image of the nucleus, and D is the quantitative analysis result of the optical density of the TDP-43 protein band in the nucleus. The results showed that the levels of TDP-43 in the cytoplasm and nucleus of the drug-treated group were close to or significantly lower than those in the nucleus of the solvent group, and the addition of EACA was able to The effect of plasminogen on TDP-43 was completely inhibited (** represents P<0.01, *** represents P<0.001), suggesting that plasminogen can degrade TDP-43 in the cytoplasm and nucleus, and this effect of plasminogen is closely related to the lysine binding site in its structure. Figure 11A-D is the result of the detection of plasminogen and plasmin activity levels in the cytoplasm and nucleus of NSC34 treated with plasminogen okadaic acid. A is the result of ELISA for the level of plasminogen in the cytoplasm, B is the result of ELISA for the level of plasminogen in the nucleus, C is the result of enzyme substrate kinetics for the level of plasmin activity in the cytoplasm, and D is the result of enzyme substrate kinetics for the level of plasmin activity in the nucleus. The results showed that the level of human plasminogen and plasmin activity in the cytoplasm and nucleus of the drug administration group was significantly higher than that in the vehicle group, and the statistical difference was significant; the addition of EACA can completely inhibit the effects of plasminogen (** represents P<0.01, *** represents P<0.001). It is suggested that plasminogen can enter cells and even the nucleus to increase plasmin activity, and the entry of plasminogen into cells and nuclei is closely related to its lysine binding activity. Figure 12 ELISA test results of plasma plasminogen levels at different time points after tail vein injection of plasminogen in SOD1-G93A mice. The results of plasma ELISA test results of SOD1-G93A mice showed that the plasma plasminogen levels of SOD1-G93A mice increased significantly after tail vein injection of 50 mg / kg and 6 mg / kg plasminogen, and the plasminogen levels in the 50 mg / kg group were significantly higher than those in the 6 mg / kg group. The plasminogen levels gradually decreased 2 hours after administration and were basically completely metabolized within 12 to 24 hours. * represents P<0.05, ** represents P<0.01, and *** represents P<0.001. The results indicate that (1) the level of plasminogen in plasma has a dose-dependent effect, and the higher the concentration of plasminogen administered, the more it aggregates; (2) the level of plasminogen in plasma has a time-dependent effect, first increasing and then gradually decreasing within 2 to 12 hours. Figure 13A-B shows the results of ELISA test for brain tissue plasminogen level at different time points and the ratio of plasminogen in brain tissue to plasminogen in plasma after intravenous injection of plasminogen in SOD1-G93A mice. A is the result of ELISA test for brain tissue plasminogen level, and B is the ratio of plasminogen in brain tissue to plasminogen in plasma. The results of ELISA test for brain plasminogen in SOD1-G93A mice showed that the level of plasminogen in brain tissue of SOD1-G93A mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the level of plasminogen in the 50mg / kg administration group was significantly higher than that in the 6mg / kg administration group. Plasminogen level gradually decreased 2 hours after administration and was basically metabolized within 12 to 24 hours. The ratio of plasminogen level in brain tissue to plasminogen level in blood was 3.47%, 4.94% and 6.79% respectively 2, 6 and 12 hours after administration of plasminogen. The results showed that (1) the administration of plasminogen under physiological and pathological conditions can promote the passage of plasminogen across the blood-brain barrier and Tissue enrichment; (2) Intravenous injection of plasminogen into mice significantly increased the level of plasminogen in brain tissue; (3) The enrichment of plasminogen in brain tissue has a time-dependent effect, first increasing, then gradually decreasing from 2 to 12 hours, and almost completely metabolized from 12 to 24 hours; (4) The enrichment of plasminogen in brain tissue has a dose-dependent effect, the higher the dose, the higher the level of plasminogen in brain tissue. ** represents P < 0.01, *** represents P < 0.001. Figure 14 ELISA test results of spinal cord tissue plasminogen levels at different time points after intravenous injection of plasminogen in SOD1-G93A mice. The results of ELISA test of SOD1-G93A mouse spinal cord plasminogen levels showed that the level of SOD1-G93A mouse spinal cord plasminogen increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the plasminogen level in the 50mg / kg group was significantly higher than that in the 6mg / kg group. Plasminogen levels gradually decreased 2 hours after administration and were basically metabolized within 12 to 24 hours. * represents P<0.05, ** represents P<0.01. The results showed that (1) plasminogen administered at physiological dose levels could cross the blood-brain barrier of SOD1-G93A mice and accumulate in the spinal cord tissue; (2) the accumulation of plasminogen in the spinal cord was dose-dependent, and the higher the dose of plasminogen administered, the greater the accumulation; and (3) the accumulation of plasminogen in the spinal cord was time-dependent, increasing first, then gradually decreasing between 2 and 12 hours, and being essentially completely metabolized within 12 to 24 hours. Figure 15A-B shows the results of plasminogen level and plasmin activity detection in brain tissue homogenate after single intravenous injection of plasminogen in SOD1-G93A mice. A is the result of ELISA test for plasminogen level, and B is the result of enzyme substrate kinetic test for plasmin activity level. The results showed that the plasminogen level and plasmin activity level in brain tissue homogenate of mice in the drug administration group were significantly higher than those in the vehicle group, and the statistical difference was significant (* represents P<0.05, *** represents P<0.001). It is suggested that intravenous administration of plasminogen can promote the increase of plasminogen level and plasmin activity in brain tissue. Figure 16 shows the results of the detection of plasminogen levels in the nuclei of brain tissue, spinal cord tissue and kidney tissue after continuous intravenous injection of plasminogen in SOD1-G93A mice for 7 days. The results showed that after 7 days of plasminogen administration, the levels of human plasminogen in the nuclei of brain tissue, spinal cord tissue and kidney tissue of SOD1-G93A mice in the administration group were significantly higher than those in the vehicle group, and the statistical difference was extremely significant (*** represents P<0.001). This suggests that intravenous administration of plasminogen can promote the increase of human plasminogen levels in the nuclei of brain tissue, spinal cord tissue and kidney tissue. Figure 17 Results of ELISA test of blood plasminogen levels at different time points after tail vein injection of plasminogen into Parkinson's model mice. The results showed that the blood plasminogen levels in the mice in the drug administration group were Significantly higher than the vehicle group, the level of plasminogen gradually decreased 2 hours after administration and was basically metabolized completely between 12 and 24 hours. *** represents P < 0.001. Figure 18 ELISA test results of blood plasminogen levels at different time points after tail vein injection of plasminogen in Parkinson's model mice. The results showed that the plasminogen level in the brain tissue of the mice in the drug group was significantly higher than that in the vehicle group. The plasminogen level gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours. The results showed that the plasminogen injected into the tail vein can cross the blood-brain barrier and promote the increase of plasminogen level in the brain tissue of Parkinson's model mice. *** represents P < 0.001. Figure 19 ELISA test results of spinal cord tissue plasminogen levels at different time points after intravenous injection of plasminogen in Parkinson's model mice. The results showed that the level of plasminogen in the spinal cord tissue of the drug-treated mice was significantly higher than that of the vehicle-treated mice. The level of plasminogen gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours. The results showed that plasminogen injected into the tail vein can cross the blood-brain barrier and promote the increase of plasminogen levels in the spinal cord tissue of Parkinson's model mice. ** represents P<0.01, *** represents P<0.001. Figure 20 The ratio of the level of plasminogen in the spinal cord or brain tissue to the level of plasminogen in the blood at different time points after the tail vein injection of plasminogen in Parkinson's model mice. The results showed that the ratio of the level of plasminogen in the spinal cord tissue to the level of plasminogen in the blood was 1.24%, 1.16% and 1.46% 2, 6 and 12 hours after the administration of plasminogen, respectively, and the ratio of the level of plasminogen in the brain tissue to the level of plasminogen in the blood was 3.47%, 4.18% and 8.51% 2, 6 and 12 hours after the administration of plasminogen, respectively. * represents P<0.05, ** represents P<0.01. The results show that the plasminogen injected by the tail vein can cross the blood-brain barrier and promote the increase of plasminogen levels in the brain and spinal cord tissues of Parkinson's model mice. Figure 21 Results of the detection of plasmin activity in brain tissue of Parkinson's model mice after tail vein injection of plasminogen. The results showed that the plasmin activity level in the brain tissue of the mice in the drug group was significantly higher than that in the vehicle group, and the statistical difference was significant. * represents P < 0.05. The results showed that plasminogen injected into the tail vein can cross the blood-brain barrier and promote the increase of plasmin activity level in the brain tissue of Parkinson's model mice. Figure 22 Results of ELISA test on plasma plasminogen levels at different time points after tail vein injection of plasminogen in FAD mice. The results of plasma ELISA test on FAD mice showed that the plasma plasminogen levels of FAD mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the plasminogen levels in the 50mg / kg group were significantly higher than those in the 6mg / kg group. Plasminogen levels gradually decreased 2 hours after administration and were basically metabolized within 12 to 24 hours. This result table The results showed that (1) the level of plasminogen in plasma has a dose-dependent effect, that is, the higher the concentration of plasminogen administered, the more plasminogen aggregates; (2) the level of plasminogen in plasma has a time-dependent effect, first increasing and then gradually decreasing within 2 to 12 hours. Figure 23A-B Results of ELISA test of brain tissue plasminogen levels at different time points after tail vein injection of plasminogen in FAD mice (A), and ratio of brain tissue plasminogen levels to blood plasminogen levels at different time points (B). The results of ELISA test of FAD mouse brain levels showed that the plasminogen levels in FAD mouse brain tissues increased significantly after tail vein injection of 50 mg / kg and 6 mg / kg plasminogen, and the plasminogen levels in the 50 mg / kg group were significantly higher than those in the 6 mg / kg group. Plasminogen levels gradually decreased 2 hours after administration and were basically metabolized completely within 12 to 24 hours. The ratio of plasminogen in brain tissue to that in blood of mice in the 6 mg / kg plasminogen group was 3.59% and 4.23% 2 and 6 hours after plasminogen injection, respectively; the ratio of plasminogen in brain tissue to that in blood of mice in the 50 mg / kg plasminogen group was 2.49%, 2.31% and 3.32% 2, 6 and 12 hours after plasminogen injection, respectively. These results indicate that (1) plasminogen administration under physiological and pathological conditions can promote plasminogen to cross the blood-brain barrier and accumulate in brain tissue; (2) intravenous injection of plasminogen into mice significantly increased the level of plasminogen in brain tissue; (3) the accumulation of plasminogen in brain tissue has a time-dependent effect, which increases first, then gradually decreases from 2 to 12 hours, and is almost completely metabolized from 12 to 24 hours; (4) the accumulation of plasminogen in brain tissue has a dose-dependent effect, and the higher the dose, the higher the level of plasminogen in brain tissue. Figure 24 Results of the enzyme substrate kinetic method to detect the activity of plasmin in brain homogenate 2 hours after tail vein injection of plasminogen in FAD mice. The results showed that the activity level of plasmin in brain tissue of FAD mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the plasminogen level in the 50mg / kg group was significantly higher than that in the 6mg / kg group. The results show that the level of plasmin in brain tissue increased significantly after plasminogen was injected into mice. In addition, the activity of plasmin in brain tissue has a dose-dependent effect. The higher the dose, the higher the level of plasminogen in brain tissue. Figure 25A-B Results of ELISA test of spinal cord tissue plasminogen levels at different time points after tail vein injection of plasminogen in FAD mice (A), and ratio of spinal cord tissue plasminogen levels to blood plasminogen levels at different time points (B). The results of ELISA test of FAD mouse spinal cord levels showed that the level of plasminogen in the spinal cord tissue of FAD mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the level of plasminogen in the 50mg / kg group was significantly higher than that in the 6mg / kg group. Plasminogen levels gradually decreased 2 hours after administration and were basically metabolized within 12 to 24 hours. The ratios of plasminogen in the spinal cord tissue to that in the blood of the mice in the 6 mg / kg plasminogen group were 0.93% and 1.62% 2 and 6 hours after plasminogen injection, respectively; the ratios of plasminogen in the spinal cord tissue to that in the blood of the mice in the 50 mg / kg plasminogen group were 0.33%, 0.40% and 1.56% 2, 6 and 12 hours after plasminogen injection, respectively. The results showed that (1) under physiological and pathological conditions, administration of plasminogen can promote plasminogen to cross the blood-brain barrier and accumulate in the spinal cord tissue; (2) intravenous injection of plasminogen into mice significantly increased the level of plasminogen in the spinal cord tissue; (3) the enrichment of plasminogen in the spinal cord tissue has a time-dependent effect, first increasing, then gradually decreasing from 2 to 12 hours, and almost completely metabolized within 12 to 24 hours; (4) the enrichment of plasminogen in the spinal cord tissue has a dose-dependent effect, and the higher the dose administered, the higher the level of plasminogen in the spinal cord tissue. Figure 26A-C shows the clinical phenotype changes of ALS patients before and after plasminogen administration. A: ALSFRS-R scores of 9 ALS patients before and after plasminogen administration, B: Maximum number of steps walked by patient 5 during the second course of medication, C: ALSFRS-R scores of 9 ALS patients during 0.5 months of plasminogen administration (indicated by solid lines) and ALSFRS-R scores of ALS patients after 6 months of Riluzole or Edaravone administration (indicated by dotted lines). DETAILED DESCRIPTION OF THE INVENTION The fibrinolytic system, also known as the fibrinolytic system, is a system composed of a series of chemical substances involved in the fibrinolysis process, mainly including plasminogen (plasminogen), plasmin, plasminogen activator, and fibrinolysis inhibitor. Plasminogen activators include tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). t-PA is a serine protease synthesized by vascular endothelial cells. t-PA activates plasminogen, and this process mainly occurs on fibrin; urokinase plasminogen activator (u-PA) is produced by renal tubular epithelial cells and vascular endothelial cells, and can directly activate plasminogen without fibrin as a cofactor. Plasminogen (PLG) is synthesized by the liver. When blood coagulates, PLG is adsorbed on the fibrin network in large quantities. Under the action of t-PA or u-PA, it is activated into plasmin, promoting fibrinolysis. Plasmin (PL) is a serine protease that has the following functions: degrade fibrin and fibrinogen; hydrolyze various coagulation factors V, VIII, X, VII, XI, II, etc.; convert plasminogen into plasmin; hydrolyze complement, etc. Fibrinolytic inhibitors: include plasminogen activator inhibitor (PAI) and α2 antiplasmin (α2-AP). PAI mainly has two forms, PAI-1 and PAI-2, which can specifically bind to t-PA in a 1:1 ratio, thereby inactivating it and activating it at the same time. PLG. α2-AP is synthesized by the liver and combines with PL in a 1:1 ratio to form a complex, inhibiting PL activity; FⅩⅢ allows α2-AP to bind to fibrin with a covalent bond, reducing the sensitivity of fibrin to the action of PL. Substances that inhibit the activity of the fibrinolytic system in the body: PAI-1, complement C1 inhibitor; α2 antiplasmin; α2 macroglobulin. The terms "plasminogen pathway activator" or "plasminogen pathway activator" of the present invention encompass components of the plasminogen activation pathway, compounds that can directly activate plasminogen or indirectly activate plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors. The term "component of the plasminogen activation pathway" or "component of the plasminogen activation pathway" according to the present invention encompasses: 1. Plasminogen, Lys-plasminogen, Glu-plasminogen, micro-plasminogen, delta-plasminogen; variants or analogs thereof; 2. Plasmin and their variants or analogs; and 3. Plasminogen activators, such as tPA and uPA, and tPA or uPA variants and analogs comprising one or more domains of tPA or uPA, such as one or more kringle domains and a proteolytic domain. The term "antagonist of a fibrinolytic inhibitor" encompasses antagonists of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin, such as antibodies to PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin. "Variants" of the above-mentioned plasminogen, plasmin, tPA and uPA include all naturally occurring human genetic variants and other mammalian forms of these proteins, as well as proteins that still have plasminogen, plasmin, tPA or uPA activity by adding, deleting and / or substituting, for example, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acids. For example, "variants" of plasminogen, plasmin, tPA, and uPA include mutational variants of these proteins obtained by, e.g., 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 conservative amino acid substitutions. The "plasminogen variants" of the present invention encompass those comprising or having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or more of the amino acid sequence shown in SEQ ID NO: 2, 6, 8, 10 or 12. or 99% sequence identity, and has plasminogen activity and / or lysine binding activity. For example, the "plasminogen variant" of the present invention can be a protein that adds, deletes and / or replaces 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acids on the basis of sequence 2, 6, 8, 10 or 12, and still has plasminogen activity and / or lysine binding activity. Specifically, the plasminogen variants of the present invention include all naturally occurring human genetic variants and other mammalian forms of these proteins, as well as mutant variants of these proteins obtained by conservative amino acid substitutions, such as 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acids. The plasminogen of the present invention can be a human plasminogen ortholog from a primate or rodent or a variant thereof that still retains plasminogen activity and / or lysine binding activity, such as the plasminogen shown in Sequence 2, 6, 8, 10 or 12, such as the human natural plasminogen shown in Sequence 2. The "analogs" of the above-mentioned plasminogen, plasmin, tPA and uPA include compounds that provide substantially similar effects to plasminogen, plasmin, tPA or uPA, respectively. The above-mentioned “variants” and “analogs” of plasminogen, plasmin, tPA and uPA encompass “variants” and “analogs” of plasminogen, plasmin, tPA and uPA comprising one or more domains (e.g., one or more kringle domains and a proteolytic domain). For example, “variants” and “analogs” of plasminogen encompass plasminogen variants and analogs comprising one or more plasminogen domains (e.g., one or more kringle (k) domains and a proteolytic domain (or serine protease domain, or plasminogen protease domain), such as mini-plasminogen. “Variants” and “analogs” of plasmin encompass plasmin “variants” and “analogs” comprising one or more plasmin domains (e.g., one or more kringle domains and a proteolytic domain), such as mini-plasmin and delta-plasmin. Whether the above-mentioned "variants" or "analogs" of plasminogen, plasmin, tPA or uPA have the activity of plasminogen, plasmin, tPA or uPA, respectively, or whether they provide substantially similar effects to plasminogen, plasmin, tPA or uPA, respectively, can be detected by methods known in the art, for example, by measuring the level of activated plasmin activity based on enzymography, ELISA (enzyme-linked immunosorbent assay) and FACS (fluorescence-activated cell sorting method), for example, reference can be made to the following literature Measured by methods described in: Ny, A., Leonardsson, G., Hagglund, AC, Hagglof, P., Ploplis, VA, Carmeliet, P. and Ny, T. (1999). Ovulation in plasminogen-deficient mice. Endocrinology 140, 5030-5035; Silverstein RL, Leung LL, Harpel PC, Nachman RL(November 1984)."Complex formation of platelet thrombospondin with plasminogen.Modulation of activation by tissue activator".J.Clin.Invest.74(5):1625–33; Gravanis I,Tsirka SE(February 2008)."Tissue-type plasminogen activator as a therapeutic target in stroke".Expert Opinion on Therapeutic Targets.12(2):159–70; Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR (Aug 1989). "Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo". Blood.74(2):722–8. In some embodiments of the present invention, the "component of the plasminogen activation pathway" of the present invention is plasminogen, selected from Glu-plasminogen, Lys-plasminogen, mini-plasminogen, micro-plasminogen, delta-plasminogen or variants thereof that retain plasminogen activity. In some embodiments, the plasminogen is natural or synthetic human plasminogen, or a conservative mutant variant thereof that still retains plasminogen activity and / or lysine binding activity, or a fragment thereof. In some embodiments, the plasminogen is a human plasminogen ortholog from a primate or rodent, or a conservative mutant variant thereof that still retains plasminogen activity and / or lysine binding activity, or a fragment thereof. In some embodiments, the amino acid sequence of the plasminogen comprises or has an amino acid sequence as shown in sequence 2, 6, 8, 10 or 12. In some embodiments, the plasminogen is a human full-length plasminogen. In some embodiments, the plasminogen is a human full-length plasminogen as shown in sequence 2. "A compound capable of directly activating plasminogen or indirectly activating plasminogen by activating an upstream component of the plasminogen activation pathway" refers to any compound capable of directly activating plasminogen or indirectly activating plasminogen by activating an upstream component of the plasminogen activation pathway, such as tPA, uPA, streptokinase, saruplase, alteplase, reteplase, tenecteplase, anistreplase, monteplase, lanoteplase, pamiplase, staphylokinase. The "antagonist of fibrinolytic inhibitor" of the present invention is a compound that antagonizes, weakens, blocks, or prevents the action of fibrinolytic inhibitor. The fibrinolytic inhibitors are, for example, PAI-1, complement C1 inhibitor, α2 antiplasmin, and α2 macroglobulin. The antagonists are, for example, antibodies to PAI-1, complement C1 inhibitor, α2 antiplasmin, or α2 macroglobulin, or antisense RNA or small RNA that blocks or downregulates the expression of PAI-1, complement C1 inhibitor, α2 antiplasmin, or α2 macroglobulin, or occupies PAI-1, complement C1 inhibitor, or "Compounds that block the binding sites of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin but do not have the functions of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin", or compounds that block the binding domain and / or active domain of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin. Plasmin is a key component of the plasminogen activator system (PA system). It is a broad-spectrum protease that can hydrolyze several components of the extracellular matrix (ECM), including fibrin, gelatin, fibronectin, laminin, and proteoglycans. In addition, plasmin can activate some metalloproteinase precursors (pro-MMPs) to form active metalloproteinases (MMPs). Therefore, plasmin is considered to be an important upstream regulator of extracellular proteolysis. Plasmin is formed by proteolysis of plasminogen by two physiological PAs: tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA). Due to the relatively high levels of plasminogen in plasma and other body fluids, it is traditionally believed that the regulation of the PA system is mainly achieved through the synthesis and activity levels of PAs. The synthesis of PA system components is strictly regulated by different factors, such as hormones, growth factors, and cytokines. In addition, there are specific physiological inhibitors of plasmin and PAs. The main inhibitor of plasmin is α2-antiplasmin. The activity of PAs is regulated by plasminogen activator inhibitor-1 (PAI-1), which inhibits both uPA and tPA, and plasminogen activator inhibitor-2 (PAI-2), which primarily inhibits uPA. Certain cells have uPA-specific cell surface receptors (uPAR) with direct hydrolytic activity on their surfaces. Plasminogen is a single-chain glycoprotein composed of 791 amino acids with a molecular weight of approximately 92 kDa. Plasminogen is mainly synthesized in the liver and exists in large quantities in the extracellular fluid. The content of plasminogen in plasma is about 2 μM. Therefore, plasminogen is a huge potential source of proteolytic activity in tissues and body fluids. There are two molecular forms of plasminogen: glutamate-plasminogen (Glu-plasminogen) and lysine-plasminogen (Lys-plasminogen). The naturally secreted and uncleaved form of plasminogen has an amino-terminal (N-terminal) glutamic acid, so it is called glutamate-plasminogen. However, in the presence of plasmin, glutamate-plasminogen is hydrolyzed at Lys76-Lys77 to become lysine-plasminogen. Compared with glutamate-plasminogen, lysine-plasminogen has a higher affinity for fibrin and can be activated by PAs at a higher rate. The Arg560-Val561 peptide bond of these two forms of plasminogen can be cleaved by uPA or tPA, resulting in the formation of a disulfide-linked two-chain protease plasmin. The amino-terminal part of plasminogen contains five homologous three rings, the so-called kringles, and the carboxyl-terminal part contains the protease domain. Some kringles contain lysine binding sites that mediate the specific interaction of plasminogen with fibrin and its inhibitor α2-AP. A recently discovered 38 kDa fragment of plasminogen, which includes kringles 1-4, is A potent inhibitor of angiogenesis. This fragment, named angiostatin, can be generated by proteolysis of plasminogen by several proteases. The main substrate of plasmin is fibrin, and the dissolution of fibrin is key to preventing pathological thrombosis. Plasmin also has substrate specificity for several components of the ECM, including laminin, fibronectin, proteoglycans, and gelatin, indicating that plasmin also plays an important role in ECM reconstruction. Indirectly, plasmin can also degrade other components of the ECM, including MMP-1, MMP-2, MMP-3, and MMP-9, by converting certain protease precursors into active proteases. Therefore, it has been suggested that plasmin may be an important upstream regulator of extracellular proteolysis. In addition, plasmin has the ability to activate certain latent forms of growth factors. In vitro, plasmin can also hydrolyze components of the complement system and release chemotactic complement fragments. "Plasmin" is a very important enzyme present in the blood, which can hydrolyze fibrin clots into fibrin degradation products and D-dimers. "Plasminogen" is the zymogen form of plasmin. According to the sequence in Swiss prot, it is composed of 810 amino acids and has a molecular weight of about 90 kD, calculated according to the amino acid sequence of natural human plasminogen containing a signal peptide (SEQ ID NO. 4). It is a glycoprotein mainly synthesized in the liver and capable of circulating in the blood. The cDNA sequence encoding the amino acid sequence is shown in SEQ ID NO. 3. The full-length plasminogen contains seven domains: a serine protease domain at the C-terminus, a Pan Apple (PAp) domain at the N-terminus, and five Kringle domains (Kringle 1-5). Referring to the sequence in Swiss prot, its signal peptide includes residues Met1-Gly19, PAp includes residues Glu20-Val98, Kringle1 includes residues Cys103-Cys181, Kringle2 includes residues Glu184-Cys262, Kringle3 includes residues Cys275-Cys352, Kringle4 includes residues Cys377-Cys454, and Kringle5 includes residues Cys481-Cys560. According to NCBI data, the serine protease domain includes residues Val581-Arg804. Glu-plasminogen is the natural full-length plasminogen, consisting of 791 amino acids (excluding the 19-amino acid signal peptide). The cDNA sequence encoding this sequence is shown in Sequence 1, and its amino acid sequence is shown in Sequence 2. In vivo, there is also a Lys-plasminogen formed by hydrolysis of the 76th-77th amino acids of Glu-plasminogen, as shown in Sequence 6, and the cDNA sequence encoding this amino acid sequence is shown in Sequence 5. Delta-plasminogen (δ-plasminogen) is a fragment of the full-length plasminogen that lacks the Kringle2-Kringle5 structure and only contains Kringle1 and a serine protease (structure) domain (also known as a proteolytic domain, or a plasminogen protease domain). The amino acid sequence of delta-plasminogen has been reported in the literature (Sequence 8), and the cDNA sequence encoding this amino acid sequence is shown in Sequence 7. Mini-plasminogen (Mini-plasminogen) consists of Kringle5 and a serine protease (structure) domain. The serine protease domain is composed of a serine protease domain, and it is reported in the literature that it includes residues Val443-Asn791 (with the Glu residue of the Glu-plasminogen sequence without a signal peptide as the starting amino acid), and its amino acid sequence is shown in Sequence 10, and the cDNA sequence encoding the amino acid sequence is shown in Sequence 9. Micro-plasminogen only contains a serine protease domain, and it is reported in the literature that its amino acid sequence includes residues Ala543-Asn791 (with the Glu residue of the Glu-plasminogen sequence without a signal peptide as the starting amino acid), and there is also a patent document CN102154253A reporting that its sequence includes residues Lys531-Asn791 (with the Glu residue of the Glu-plasminogen sequence without a signal peptide as the starting amino acid). The sequence of this patent refers to the patent document CN102154253A, and its amino acid sequence is shown in Sequence 12, and the cDNA sequence encoding the amino acid sequence is shown in Sequence 11. The "plasmin" of the present invention can be used interchangeably with "plasmin" and "fibrinolytic enzyme" and have the same meaning; the "plasminogen" can be used interchangeably with "plasmin" and "fibrinolytic enzyme" and have the same meaning. In the present application, the meaning or activity of "lack of" plasminogen is that the content of plasminogen in the subject's body is lower than that of a normal person, low enough to affect the normal physiological function of the subject; the meaning or activity of "absence" of plasminogen is that the content of plasminogen in the subject's body is significantly lower than that of a normal person, and even the activity or expression is extremely low, and normal physiological function can only be maintained through exogenous supply. Those skilled in the art will appreciate that all technical solutions of the plasminogen of the present invention are applicable to plasmin, and therefore, the technical solutions described in the present invention cover plasminogen and plasmin. During the circulation process, plasminogen adopts a closed inactive conformation, but when bound to a thrombus or cell surface, it is converted into an active plasmin in an open conformation under the mediation of a plasminogen activator (PA). Active plasmin can further hydrolyze fibrin clots into fibrin degradation products and D-dimers, thereby dissolving thrombi. Among them, the PAp domain of plasminogen contains an important determinant cluster that maintains plasminogen in an inactive closed conformation, while the KR domain can bind to lysine residues present on receptors and substrates. A variety of enzymes that can act as plasminogen activators are known, including: tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and coagulation factor XII (Hageman factor), etc. "Plasminogen active fragments" in the present application include 1) active fragments in plasminogen protein that can bind to the target sequence in the substrate, also known as lysine binding fragments, such as fragments containing Kringle 1, Kringle 2, Kringle 3, Kringle 4 and / or Kringle 5 (the structure of the plasminogen is described in Aisina RB, Mukhametova LI. Structure and function of plasminogen / plasmin system [J]. Russian Journal of Bioorganic Chemistry, 2014, 40 (6): 590-605); 2) active fragments that play a proteolytic function in plasminogen protein. Segment, for example, a fragment containing the plasminogen activity (proteolytic function) shown in sequence 14; 3) In the plasminogen protein, a fragment having both the activity of binding to the target sequence in the substrate (lysine binding activity) and the plasminogen activity (proteolytic function). In some embodiments of the present application, the plasminogen is a protein containing the plasminogen active fragment shown in sequence 14. In some embodiments of the present application, the plasminogen is a protein containing the lysine binding fragment of Kringle 1, Kringle 2, Kringle 3, Kringle 4 and / or Kringle 5. In some embodiments, the plasminogen active fragment of the present application comprises sequence 14, and a protein having an amino acid sequence with at least 80%, 90%, 95%, 96%, 97%, 98%, 99% homology to sequence 14. Therefore, the plasminogen described in the present invention includes a protein containing the plasminogen active fragment and still retaining the plasminogen activity. In some embodiments, the plasminogen of the present application comprises Kringle 1, Kringle 2, Kringle 3, Kringle 4 and / or Kringle 5, or a protein that has at least 80%, 90%, 95%, 96%, 97%, 98%, 99% homology to Kringle 1, Kringle 2, Kringle 3, Kringle 4 or Kringle 5 and still has lysine binding activity. At present, the methods for measuring plasminogen in blood and its activity include: detection of tissue plasminogen activator activity (t-PAA), detection of plasma tissue plasminogen activator antigen (t-PAAg), detection of plasma tissue plasminogen activity (plgA), detection of plasma tissue plasminogen antigen (plgAg), detection of plasma tissue plasminogen activator inhibitor activity, detection of plasma tissue plasminogen activator inhibitor antigen, and detection of plasma plasmin-antiplasmin complex (PAP). The most commonly used detection method is the chromogenic substrate method: adding streptokinase (SK) and chromogenic substrate to the test plasma, PLG in the test plasma is converted into PLM under the action of SK, and the latter acts on the chromogenic substrate, which is then measured by a spectrophotometer, and the increase in absorbance is proportional to the activity of plasminogen. In addition, immunochemical method, gel electrophoresis, immunoturbidimetry, radial immunodiffusion method, etc. can also be used to measure the activity of plasminogen in blood. "Orthologs" refer to homologs between different species, including both protein homologs and DNA homologs, also known as orthologs and vertical homologs. They specifically refer to proteins or genes evolved from the same ancestral gene in different species. The plasminogen of the present invention includes human natural plasminogen, and also includes orthologs or orthologs of plasminogen from different species that have plasminogen activity. "Conservative substitution variants" refer to variants in which a given amino acid residue is changed but does not change the overall conformation and function of the protein or enzyme, including but not limited to replacing an amino acid in the amino acid sequence of the parent protein with an amino acid of similar properties (such as acidity, basicity, hydrophobicity, etc.). The properties of amino acids are well known. For example, arginine, histidine and lysine are hydrophilic basic amino acids and can be interchanged. Similarly, isoleucine is a hydrophobic amino acid and can be replaced by leucine, methionine or valine. Therefore, the similarity of two proteins or amino acid sequences with similar functions may be different. For example, 70% to 99% similarity (identity) based on the MEGALIGN algorithm. "Conservative substitution variants" also include polypeptides or enzymes with more than 60% amino acid identity determined by BLAST or FASTA algorithms, and better if it can reach more than 75%, preferably more than 85%, and even more than 90% is the best, and compared with the natural or parent protein or enzyme, it has the same or substantially similar properties or functions. "Pathological TDP-43 protein" is a term relative to "physiologically functional TDP-43 protein". Physiologically functional TDP-43 protein refers to a TDP-43 protein that is in a state where it can exhibit its desired function in the in vivo cellular environment. In contrast, "pathological TDP-43 protein" refers to a TDP-43 protein that is unable to exhibit its desired function in the in vivo cellular environment. Examples of pathological TDP-43 proteins include, but are not limited to: TDP-43 proteins that have mutated and lost their physiological functions (e.g., lost more than 50%, 60%, 70%, 80%, 90% of their relevant physiological functions), TDP-43 proteins that form protein aggregates, misfolded TDP-43 proteins, abnormally modified TDP-43 proteins (including hyperphosphorylation, ubiquitination, acetylation, and C-terminal fragments cleaved by proteolysis), and TDP-43 proteins that have undergone protein denaturation. Another characteristic feature of TDP-43 pathological conditions is the redistribution and accumulation of TDP-43 from the nucleus to the cytoplasm, and such proteins are also included in the scope of pathological TDP-43 proteins of the present application. In the present application, in the context of plasminogen "promoting TDP-43 (protein) degradation", it means that plasminogen promotes the degradation of pathological TDP-43 (protein). "Isolated" plasminogen refers to plasminogen protein that has been separated and / or recovered from its natural environment. In some embodiments, the plasminogen is purified (1) to a purity of greater than 90%, greater than 95%, or greater than 98% (by weight) as determined by the Lowry method, for example, greater than 99% (by weight), (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequencer, or (3) to homogeneity as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing or non-reducing conditions using Coomassie blue or silver stain. Isolated plasminogen also includes plasminogen prepared from recombinant cells by bioengineering techniques and isolated by at least one purification step. The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymeric form of amino acids of any length, which may include genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with modified peptide backbones. Included are fusion proteins, including but not limited to fusion proteins with heterologous amino acid sequences, fusions with heterologous and homologous leader sequences (with or without an N-terminal methionine residue); and the like. "Percentage (%) of amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after introducing gaps, if necessary, to achieve maximum percentage sequence identity, and without considering any conservative substitutions as part of the sequence identity. Contrast for the purpose of determining percentage amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. One skilled in the art can determine suitable parameters for aligning sequences, including any algorithm required to achieve maximum alignment over the entire length of the compared sequences. However, for purposes of the present invention, percentage values ​​of amino acid sequence identity are generated using the sequence comparison computer program ALIGN-2. In the case of using ALIGN-2 to compare amino acid sequences, the % amino acid sequence identity of a given amino acid sequence A relative to a given amino acid sequence B (or may be expressed as a given amino acid sequence A having or comprising a certain % amino acid sequence identity relative to, with, or to a given amino acid sequence B) is calculated as follows: Multiply the fraction X / Y by 100 where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not be equal to the % amino acid sequence identity of B to A. Unless expressly stated otherwise, all % amino acid sequence identity values ​​used herein are obtained as described in the preceding paragraph using the ALIGN-2 computer program. The terms "individual," "subject," and "patient" are used interchangeably herein to refer to mammals, including but not limited to murines (rats, mice), non-human primates, humans, dogs, cats, ungulates (e.g., horses, cattle, sheep, pigs, goats), and the like. "Therapeutically effective amount" or "effective amount" refers to the amount of plasminogen that is sufficient to achieve the described prevention and / or treatment of the disease when administered to a mammal or other subject for the treatment of a disease."Therapeutically effective amount" will vary depending on the plasminogen used, the severity of the disease and / or its symptoms of the subject to be treated, and the age, weight, etc. The term "treating" or "treatment" of a disease state includes inhibiting or arresting the development of the disease state or its clinical symptoms, or alleviating the disease state or symptoms such that the disease state or its clinical symptoms regress temporarily or permanently. Preparation of plasminogen of the present invention Plasminogen can be isolated and purified from nature for further therapeutic use, or it can be synthesized by standard chemical peptide synthesis techniques. When synthesizing polypeptides by chemical synthesis, they can be synthesized via liquid or solid phase. Solid phase peptide synthesis (SPPS) (wherein the C-terminal amino acid of the sequence is attached to an insoluble support, followed by sequential addition of the remaining amino acids in the sequence) is a method suitable for chemical synthesis of plasminogen. Various forms of SPPS, such as Fmoc and Boc can be used to synthesize plasminogen. Techniques for solid phase synthesis are described in Barany and Solid-Phase Peptide Synthesis; pages 3-284 in The Peptides: Analysis, Synthesis, Biology. Vol. 2: Special Methods in Peptide Synthesis, Part A., Merrifield, et al. J. Am. Chem. Soc., 85: 2149-2156 (1963); Stewart et al., Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem. Co., Rockford, 111. (1984); and Ganesan A. 2006 Mini Rev. Med Chem. 6: 3-10 and Camarero JA et al. 2005 Protein Pept Lett. 12: 723-8. Briefly, small insoluble porous beads are treated with functional units on which peptide chains are built. After repeated cycles of coupling / deprotection, the attached solid phase free N-terminal amine is coupled to a single N-protected amino acid unit. This unit is then deprotected, exposing a new N-terminal amine that can be attached to another amino acid. The peptide remains fixed on the solid phase and is later cleaved off. Standard recombinant methods can be used to produce plasminogen of the present invention. For example, a nucleic acid encoding plasminogen is inserted into an expression vector so that it is operably linked to a regulatory sequence in the expression vector. Expression regulatory sequences include, but are not limited to, promoters (e.g., naturally associated or heterologous promoters), signal sequences, enhancer elements, and transcription termination sequences. Expression regulation can be a eukaryotic promoter system in a vector that is capable of transforming or transfecting eukaryotic host cells (e.g., COS or CHO cells). Once the vector is incorporated into a suitable host, the host is maintained under conditions suitable for high-level expression of the nucleotide sequence and collection and purification of plasminogen. Suitable expression vectors typically replicate in the host organism as an episome or as an integrated part of the host chromosomal DNA. Typically, expression vectors contain selection markers (e.g., ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance or neomycin resistance) to facilitate detection of those cells transformed with the desired DNA sequence from an exogenous source. Escherichia coli is an example of a prokaryotic host cell that can be used to clone plasminogen encoding polynucleotides. Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species. In these prokaryotic hosts, expression vectors can also be generated, which will generally contain expression control sequences (e.g., replication origins) that are compatible with the host cells. In addition, there are many well-known promoters, such as the lactose promoter system, the tryptophan (trp) promoter system, the beta-lactamase promoter system, or the promoter system from bacteriophage lambda. The promoter will generally control expression, optionally in the case of an operator gene sequence, and have a ribosome binding site sequence, etc., to initiate and complete transcription and translation. Other microorganisms, such as yeast, can also be used for expression. Yeast (e.g., S. cerevisiae) and Pichia are examples of suitable yeast host cells, with suitable vectors having expression control sequences (e.g., promoters), replication origins, termination sequences, etc. as required. Typical promoters include 3-phosphoglycerate kinase and other glycolytic enzymes. Inducible yeast promoters include promoters from alcohol dehydrogenase, isocytochrome C, and enzymes responsible for maltose and galactose utilization, among others. In addition to microorganisms, mammalian cells (e.g., mammalian cells cultured in in vitro cell culture) can also be used to express and produce the plasminogen of the present invention (e.g., a polynucleotide encoding plasminogen). See Winnacker, From Genes to Clones, VCH Publishers, NY, NY (1987). Suitable mammalian host cells include CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, and transformed B cells or hybridomas. Expression vectors for these cells can contain expression control sequences, such as replication origins, promoters and enhancers (Queen et al., Immunol. Rev. 89: 49 (1986)), as well as necessary processing information sites, such as ribosome binding sites, RNA splicing sites, polyadenylation sites, and transcription terminator sequences. Examples of suitable expression control sequences are promoters derived from immunoglobulin genes, SV40, adenovirus, bovine papilloma virus, cytomegalovirus, etc. See Co et al., J. Immunol. 148: 1149 (1992). Once synthesized (chemically or recombinantly), the plasminogen of the present invention can be purified according to standard procedures in the art, including ammonium sulfate precipitation, affinity columns, column chromatography, high performance liquid chromatography (HPLC), gel electrophoresis, etc. The plasminogen is substantially pure, e.g., at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or 98% to 99% pure or more, e.g., free of contaminants, such as cellular debris, macromolecules other than plasminogen, etc. Pharmaceutical preparations Plasminogen having the desired purity can be mixed with an optional pharmaceutical carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)) The therapeutic formulation is prepared by forming a lyophilized preparation or an aqueous solution. Acceptable carriers, excipients, stabilizers are non-toxic to recipients at the dosages and concentrations used, and include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; chloride), benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, fucose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and / or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The formulations of the present invention may also contain more than one active compound required for the specific condition to be treated, preferably those with complementary activities and no side effects between them, for example, antihypertensive drugs, antiarrhythmic drugs, drugs for treating diabetes, etc. The plasminogen of the present invention can be encapsulated in microcapsules prepared by techniques such as coacervation or interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules placed in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. These techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). The plasminogen of the present invention for in vivo administration must be sterile. This can be easily achieved by filtering through a sterile filtration membrane before or after lyophilization and reconstitution. The plasminogen of the present invention can be prepared into a sustained-release preparation. Suitable examples of sustained-release preparations include solid hydrophobic polymer semipermeable matrices having a certain shape and containing glycoproteins, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (such as poly (2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater. Res., 15: 167-277 (1981); Langer, Chem. Tech., 12: 98-105 (1982)) or poly (vinyl alcohol), polylactide (U.S. Pat. No. 3773919, EP 58,481), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid (Sidman, et al., Biopolymers 22: 547 (1983)), non-degradable ethylene-vinyl acetate (Langer, et al., supra), or degradable lactic acid-glycolic acid copolymers such as Lupron. DepotTM (injectable microspheres composed of lactic acid-co-glycolic acid and leucylproline (leuprolide) acetate), and poly-D-(-)-3-hydroxybutyric acid. Polymers such as ethylene-vinyl acetate and lactic acid-co-glycolic acid can release molecules for a sustained period of 100 Some hydrogels release proteins for more than 10 days, while some release proteins for a shorter time. Rational strategies for protein stabilization can be designed based on the relevant mechanisms. For example, if the mechanism of coagulation is found to be the formation of intermolecular SS bonds through the interchange of thiodisulfide bonds, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling humidity, using appropriate additives, and developing specific polymer matrix compositions. Administration and Dosage Administration of the pharmaceutical composition of the invention can be achieved by different ways, for example, intravenously, intraperitoneally, subcutaneously, intracranially, intrathecally, intraarterially (eg via the carotid artery), intramuscularly. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride or fixed oils. Intravenous vehicles include liquid and nutritional supplements, electrolyte supplements, etc. Preservatives and other additives may also be present, such as, for example, antimicrobial agents, antioxidants, chelating agents and inert gases, etc. Medical personnel can determine dosage regimens based on various clinical factors. As known in the medical field, the dosage of any patient depends on a variety of factors, including the patient's body shape, body surface area, age, specific compound to be applied, sex, number of applications and path, overall health, and other drugs applied simultaneously. The dosage range of the pharmaceutical composition comprising plasminogen of the present invention can be about 0.0001 to 2000mg / kg per day, or about 0.001 to 500mg / kg (e.g., 0.02mg / kg, 0.25mg / kg, 0.5mg / kg, 0.75mg / kg, 10mg / kg, 50mg / kg, etc.) subject body weight. For example, the dosage can be 1mg / kg body weight or 50mg / kg body weight or in the range of 1-50mg / kg, or at least 1mg / kg. Dosages higher or lower than this exemplary range are also included, particularly in view of the above-mentioned factors. Intermediate doses in the above range are also included within the scope of the present invention. Subjects can apply such dosages every day, every other day, every week, or according to any other schedule determined by empirical analysis. An exemplary dosage schedule includes 1-10 mg / kg on consecutive days. During the administration of the drug of the present invention, it is necessary to evaluate the therapeutic effect and safety in real time. Products or kits One embodiment of the present invention relates to an article of manufacture or kit comprising the plasminogen or plasmin of the present invention which can be used to treat cardiovascular disease and related conditions caused by diabetes. The article of manufacture preferably includes a container, a label or a package insert. Suitable containers include bottles, vials, syringes, etc. The container can be made of various materials such as glass or plastic. The container contains a composition, the composition The composition can effectively treat the disease or condition of the present invention and has a sterile access port (for example, the container can be an intravenous solution bag or a vial containing a stopper that can be penetrated by a hypodermic injection needle). At least one active agent in the composition is plasminogen / plasmin. The label on or attached to the container indicates that the composition is used to treat cardiovascular disease caused by diabetes and related conditions described in the present invention. The product may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and glucose solution. It may further include other substances required from a commercial and user perspective, including other buffers, diluents, filters, needles and syringes. In addition, the product includes a package insert with instructions for use, including, for example, instructing the user of the composition to administer the plasminogen composition and other drugs for treating concomitant diseases to the patient. The "muscle atrophy" of this application refers to the reduction in the amount of muscle tissue, structural abnormality, reduction or loss and / or functional abnormality, weakening or loss caused by various reasons. The causes of muscle atrophy are mainly various muscle diseases or trauma, including syringomyelia, myelitis, radiculoarthropathy, basal arachnoiditis, brainstem lesions, and brain and spinal neuropathy. Example The human plasminogen used in all the following examples was from donor plasma, based on the literature: Kenneth C Robbins, Louis Summaria, David Elwyn et al. Further Studies on the Purification and Characterization of Human Plasminogen and Plasmin. Journal of Biological Chemistry, 1965, 240 (1): 541-550; Summaria L, Spitz F, Arzadon L et al. Isolation and characterization of the affinity chromatography forms of human Glu- and Lys-plasminogens and plasmins. J Biol Chem. 1976 Jun 25; 251 (12): 3693-9; HAGAN JJ, ABLONDI FB, DE RENZO EC. Purification and biochemical properties of human plasminogen. J Biol Chem. 1960 Apr; 235: 1005-10 [1-3] described method and process optimization, purified from human donor plasma, wherein human Lys-plasminogen (Lys-plasminogen) and Glu-plasminogen (Glu-plasminogen)> 98%. Example Example 1 Plasminogen promotes the cleavage of pathological TDP-43 protein in normal mouse brain homogenate Four C57BL / 6J male mice aged 11 to 12 weeks and weighing 18 to 25 g were sacrificed and the whole brain was removed and weighed. 1× ​​PBS (Thermo Fisher, pH 7.4; 10010-031, homogenize at 4°C (1 min, 3-4 times), centrifuge at 4°C (12000 rpm, 20 min) after homogenization, take the supernatant, i.e. brain homogenate, and place it in a new EP tube. Eppendorf (EP) tubes were set as ① blank group, ② blank control group, ③ vehicle control group, and ④ plasminogen group, with 5 parallels in each group. The blank group was added with 21.5 μL of normal saline, 4.6 μL of solvent solution (10 mM sodium citrate, 2% arginine hydrochloride, 3% mannitol, pH 7.4), and 23.9 μL of mouse brain homogenate; the blank control group was added with 21.5 μL of normal saline, 2.3 μL of plasminogen solution (2 mg / mL), and 23.9 μL of mouse brain homogenate; the vehicle control group was added with 20.5 μL of TDP-43 (Nanjing GenScript Biotechnology Co., Ltd., custom-expressed human TDP-43, C134WHE160-2 / P5HF001, 1.05 mg / mL), 4.6 μL of solvent solution, and 23.9 μL of mouse brain homogenate; the plasminogen group was added with 20.5 μL of TDP-43 (1.05 mg / mL), 2.3 μL of plasminogen solution (2 mg / mL), and 23.9 μL of mouse brain homogenate. After adding the samples of each group, they were incubated at 37°C for 3 h and then 50 μL of 0.1% trifluoroacetic acid solution was added to terminate the reaction. Prepare 12% gel according to the SDS-PAGE gel preparation instructions. Mix each group of samples with 4× loading buffer (TaKaRa, e2139) at a volume ratio of 3:1, heat at 100℃ for 5min, centrifuge for 2min after cooling, and then take 20μL for loading. The electrophoresis conditions are 30V for 45min, and then 100V for electrophoresis to the bottom of the gel. After the electrophoresis is completed, the gel is peeled and transferred to an activated PVDF membrane (GE, A29433753) at 15V for 2.5h. The transferred PVDF membrane was immersed in blocking solution (5% skim emulsion) and blocked overnight in a 4°C refrigerator. After washing 4 times with TBST (0.01M Tris-NaCl, pH 7.6 buffer), rabbit anti-human TDP-43 antibody (Proteintech (China), 12892-1-AP) and cyclophilin antibody were added and incubated at room temperature for 1.5 h. After washing 4 times with TBST, goat anti-rabbit IgG (HRP) antibody (Abcam, ab6721) secondary antibody was added and incubated at room temperature for 1 h. After washing 4 times with TBST, the PVDF membrane was placed on a clean imaging plate, Immobilon Western HRP Substrate (MILLIPORE, WBKLS0100) was added for color development, and photos were taken under a biomolecular imager and quantitatively analyzed using Image J. The results showed that the molecular weight of the recombinant TDP-43 protein monomer was about 43kDa, the molecular weight of the high molecular weight TDP-43 protein (HMW) was >55kDa, and the molecular weight of the low molecular weight TDP-43 fragment (LMW) was <40kDa. In addition, in the normal mouse brain homogenate, the amount of TDP-43 monomer, HMW and LMW in the plasminogen group was significantly lower than that in the vehicle control group, and the difference was extremely significant (*** represents P <0.001, * represents P <0.05) (Figure 2). This suggests that plasminogen can promote the cleavage of TDP-43 in normal mouse brain homogenate. Example 2 Plasminogen promotes the cleavage of pathological TDP-43 protein in the brain homogenate of amyotrophic sclerosis model mice Four B6.Cg-Tg(SOD1-G93A)1Gur / J transgenic male mice (referred to as SOD1-G93A transgenic mice) were killed and the whole brain was taken out and weighed. 1×PBS (Thermo Fisher, pH7.4; 10010-031) was added at 150 mg tissue / mL PBS and homogenized at 4°C (1 min, 3-4 times). After homogenization, the supernatant, i.e., the brain homogenate, was taken out and placed in a new EP tube. Eppendorf (EP) tubes were set as ① blank group, ② blank control group, ③ vehicle control group, and ④ plasminogen group, with 5 parallels in each group. The blank group was added with 21.5 μL of normal saline, 4.6 μL of solvent solution (10 mM sodium citrate, 2% arginine hydrochloride, 3% mannitol, pH 7.4), and 23.9 μL of mouse brain homogenate; the blank control group was added with 21.5 μL of normal saline, 2.3 μL of plasminogen solution (2 mg / mL), and 23.9 μL of mouse brain homogenate; the vehicle control group was added with 20.5 μL of TDP-43 (Nanjing GenScript Biotechnology Co., Ltd., custom-expressed human TDP-43, C134WHE160-2 / P5HF001, 1.05 mg / mL), 4.6 μL of solvent solution, and 23.9 μL of mouse brain homogenate; the plasminogen group was added with 20.5 μL of TDP-43 (1.05 mg / mL), 2.3 μL of plasminogen solution (2 mg / mL), and 23.9 μL of mouse brain homogenate. After adding the samples of each group, they were incubated at 37°C for 3 h and then 50 μL of 0.1% trifluoroacetic acid solution was added to terminate the reaction. Prepare 12% gel according to the SDS-PAGE gel preparation instructions. Mix each group of samples with 4× loading buffer (TaKaRa, e2139) at a volume ratio of 3:1, heat at 100℃ for 5min, centrifuge for 2min after cooling, and then take 20μL for loading. The electrophoresis conditions are 30V for 45min, and then 100V for electrophoresis to the bottom of the gel. After the electrophoresis is completed, the gel is peeled and transferred to an activated PVDF membrane (GE, A29433753) at 15V for 2.5h. The transferred PVDF membrane was immersed in blocking solution (5% skim emulsion) and blocked overnight in a 4°C refrigerator. After washing 4 times with TBST (0.01M Tris-NaCl, pH 7.6 buffer), rabbit anti-human TDP-43 antibody (Proteintech, 12892-1-AP) and cyclophilin antibody were added and incubated at room temperature for 1.5 h. After washing 4 times with TBST, goat anti-rabbit IgG (HRP) antibody (Abcam, ab6721) secondary antibody was added and incubated at room temperature for 1 h. After washing 4 times with TBST, the PVDF membrane was placed on a clean imaging plate, Immobilon Western HRP Substrate (MILLIPORE, WBKLS0100) was added for color development, and photos were taken under a biomolecular imager and quantitatively analyzed using Image J. The results showed that the molecular weight of the recombinant TDP-43 protein monomer was about 43kDa, the molecular weight of the high molecular weight TDP-43 protein (HMW) was >55kDa, and the molecular weight of the low molecular weight TDP-43 fragment (LMW) was <40kDa. In addition, in the brain homogenate of ALS model mice, the amount of TDP-43 monomer, HMW and LMW in the plasminogen group was significantly lower than that in the vehicle control. The difference between the two groups was extremely significant (*** represents P < 0.001, ** represents P < 0.01) (Figure 3). This suggests that plasminogen can promote the cleavage of TDP-43 in the brain homogenate of ALS model mice. Example 3 Plasminogen promotes TDP-43 degradation in spinal cord tissue of amyotrophic lateral sclerosis model mice Six SOD1-G93A mice aged 10-15 weeks were randomly divided into two groups, three in the vehicle control group and three in the drug administration group. The vehicle control group mice were injected with the vehicle at 5 ml / kg of tail vein, and the drug administration group mice were injected with plasminogen (10 mg / ml) at 50 mg / kg of body weight of tail vein. The mice were killed 24 hours after administration, and the spinal cord was collected. After homogenization, TDP-43 western blot was performed. The results showed that the amount of TDP-43 monomer and low molecular weight TDP-43 in the spinal cord tissue of mice in the drug administration group was significantly lower than that in the vehicle group, and the statistical difference was significant (* represents P<0.05) (Figure 4). This indicates that plasminogen can promote the degradation of TDP-43 in the spinal cord tissue of mice with ALS model. Example 4 Plasminogen promotes TDP-43 degradation in brain tissue of amyotrophic lateral sclerosis model mice Nine 6-7 week old C57BL / 6J female mice were taken and weighed before modeling. After weighing, all mice were randomly divided into two groups: blank control group (3 mice) and model group (6 mice). After grouping, mice in sham operation group and model group were anesthetized by intraperitoneal injection of tribromoethanol, with an anesthetic dose of 20mL / kg. Model mice were located in the hippocampus according to the mouse stereotaxic atlas (according to the coordinates of the bregma: AP-2.54mm, ML±2mm, DV-2.4mm), and each mouse was slowly microinjected bilaterally. The sham operation group mice were only drilled at the coordinate location point and no injection was performed [4]. The model group mice were injected with TDP-43 solution at an injection rate of 0.5μL / min and an injection volume of 3μL / side. After the injection, the syringe stayed for 5min and then slowly withdrew. Three days after the brain localization injection, all mice were weighed, and the model group mice were intraperitoneally injected with 5 mg / kg LPS solution according to their body weight. Then the model group mice were randomly divided into two groups, 3 in the drug group and 3 in the vehicle group. 24 hours after LPS injection, the sham operation group mice and the vehicle group mice were injected with 5 mL / kg of the vehicle through the tail vein, and the drug group mice were injected with 50 mg / kg of plasminogen through the tail vein. The drugs were administered for 3 consecutive days. Two hours after the third administration, the mice were killed and brain tissues were obtained. TDP-43 western blot detection was performed after homogenization. The results showed that the amount of TDP-43 monomer and low molecular weight TDP-43 in the brain tissue of mice in the drug administration group was significantly lower than that in the vehicle group, and the statistical difference was significant (* represents P<0.05) (Figure 5). This shows that plasminogen can promote the degradation of TDP-43 in the brain tissue of mice with ALS model. Example 5 Plasminogen is enriched in the spinal cord tissue of amyotrophic lateral sclerosis model mice and co-localizes with TDP-43 in cells Five wild-type male mice and nine male SOD1-G93A mice of similar age were selected. Wild-type mice were used as the blank control group, and SOD1-G93A mice were observed and recorded from the 14th week when their hind legs trembled. The onset time of each mouse was recorded, and the drug administration began 14 days after the onset. All mice were randomly divided into a vehicle group and a drug administration group according to the onset of the disease. Among them, there were 5 mice in the vehicle group, and 0.1 ml / mouse vehicle (sodium citrate buffer) was injected into the tail vein every day; 4 mice in the drug administration group were injected with 1 mg / 0.1 ml / mouse plasminogen into the tail vein every day, and the drug administration was continuous in the SPF environment. The samples were collected at the end of death, and the longest drug administration was 61 days. The spinal cord tissue was fixed in formalin fixative. The fixed tissue was dehydrated by alcohol gradient and transparentized by xylene before paraffin embedding. The thickness of the tissue section was 3 μm, and the sections were washed once after dewaxing and rehydration. The sections were immersed in the antigen retrieval working solution (0.01M sodium citrate buffer) and microwave repaired, preheated for 5 minutes, high heat for 2 minutes, and low heat for 15 minutes. The tissue was circled with a PAP pen, incubated with 3% hydrogen peroxide for 15 minutes, and washed twice with 0.01M PBS for 5 minutes each time. 5% normal sheep serum (Vector laboratories, Inc., USA) was blocked for 30 minutes; after the time was up, the sheep serum was discarded, and anti-plasminogen antibody (self-produced) was added dropwise, incubated at 4°C overnight, and washed twice with 0.01M PBS for 5 minutes each time. The goat anti-rabbit IgG (HRP) antibody (Abcam) secondary antibody was incubated at room temperature for 1 hour, and washed twice with 0.01M PBS for 5 minutes each time. According to the instructions of the XTSA520 IHC kit (Alpha X Biotech, AXT6202500), the corresponding anti-plasminogen secondary antibody was used for green fluorescence color development. Washed 3 times with PBS for 5 minutes each time. Repeat the above antigen retrieval and blocking operations, then stain with anti-TDP-43 antibody (Proteintech, 12892-1-AP) and incubate at 37°C for 1 hour. Wash with PBS 3 times, 5 minutes each time. Incubate with goat anti-rabbit IgG (HRP) antibody (Abcam) secondary antibody at room temperature for 1 hour, wash with 0.01M PBS 2 times, 5 minutes each time. Incubate with goat anti-rabbit IgG (HRP) antibody (Abcam) secondary antibody at room temperature for 1 hour, wash with 0.01M PBS 2 times, 5 minutes each time. Perform red fluorescence color development of the corresponding anti-TDP-43 secondary antibody according to the instructions of the XTSA620 IHC kit (Alpha X Biotech, AXT6502500). Wash with PBS 3 times, 5 minutes each time. Perform DAPI (BOSTER, 11K16B77) nuclear staining. Wash with PBS 3 times, 5 minutes each time. Dehydrate with gradient alcohol, transparentize with xylene and seal with neutral gum, and observe and photograph the sections under a 400x optical microscope. The results showed that the positive staining of plasminogen (green fluorescence) in the spinal cord tissue of the drug-treated group was significantly higher than that of the vehicle group, indicating that the drug-treated plasminogen could enter the spinal cord tissue and accumulate in the spinal cord tissue. In addition, plasminogen was present in the cytoplasm (as shown in △) and the nucleus (as shown in Plasminogen co-localizes with TDP-43 (red fluorescence) in the cytoplasm (▲) and in the nucleus ( The TDP-43 level in the spinal cord tissue of the drug-treated group was lower than that of the vehicle group, and the co-localization of plasminogen and TDP-43 in the drug-treated group was more than that in the vehicle group (Figure 6). Plasminogen can enter the spinal cord tissue, enter the cells, co-localize with TDP-43, and degrade TDP-43. Example 6 Plasminogen is enriched in the muscle tissue of amyotrophic lateral sclerosis model mice and co-localizes with TDP-43 in cells Five wild-type male mice and nine male SOD1-G93A mice of similar age were selected. Wild-type mice were used as the blank control group, and SOD1-G93A mice were observed and recorded from the 14th week when their hind legs trembled. The onset time of each mouse was recorded, and the drug administration began 14 days after the onset. All mice were randomly divided into a vehicle group and a drug administration group according to the onset of the disease. Among them, there were 5 mice in the vehicle group, and 0.1 ml / mouse vehicle (sodium citrate buffer) was injected into the tail vein every day; 4 mice in the drug administration group were injected with 1 mg / 0.1 ml / mouse plasminogen into the tail vein every day, and the drug administration was continuous in an SPF environment. The samples were collected at the end of death, and the longest drug administration was 61 days. The gluteal muscle tissue was fixed in formalin fixative. The fixed tissue was dehydrated by alcohol gradient and transparentized with xylene before paraffin embedding. The thickness of the tissue section was 3 μm, and the sections were washed once after dewaxing and rehydration. The sections were immersed in the antigen retrieval working solution (0.01M sodium citrate buffer) and microwave repaired, preheated for 5 minutes, high heat for 2 minutes, and low heat for 15 minutes. The tissue was circled with a PAP pen, incubated with 3% hydrogen peroxide for 15 minutes, and washed twice with 0.01M PBS for 5 minutes each time. 5% normal sheep serum (Vector laboratories, Inc., USA) was blocked for 30 minutes; after the time was up, the sheep serum was discarded, and anti-plasminogen antibody (self-produced) was added dropwise, incubated at 4°C overnight, and washed twice with 0.01M PBS for 5 minutes each time. The goat anti-rabbit IgG (HRP) antibody (Abcam) secondary antibody was incubated at room temperature for 1 hour, and washed twice with 0.01M PBS for 5 minutes each time. According to the instructions of the XTSA520 IHC kit (Alpha X Biotech, AXT6202500), the corresponding anti-plasminogen secondary antibody was used for green fluorescence color development. Washed 3 times with PBS for 5 minutes each time. Repeat the above antigen retrieval and blocking operations, then stain with anti-TDP-43 antibody (Proteintech, 12892-1-AP) and incubate at 37°C for 1 hour. Wash with PBS 3 times, 5 minutes each time. Incubate with goat anti-rabbit IgG (HRP) antibody (Abcam) secondary antibody at room temperature for 1 hour, wash with 0.01M PBS 2 times, 5 minutes each time. Incubate with goat anti-rabbit IgG (HRP) antibody (Abcam) secondary antibody at room temperature for 1 hour, wash with 0.01M PBS 2 times, 5 minutes each time. Perform red fluorescence color development of the corresponding anti-TDP-43 secondary antibody according to the instructions of the XTSA620 IHC kit (Alpha X Biotech, AXT6502500). Wash with PBS 3 times, 5 minutes each time. Perform DAPI (BOSTER, 11K16B77) nuclear staining. Wash with PBS 3 times, 5 minutes each time. Dehydrate with gradient alcohol, transparentize with xylene and seal with neutral gum, and observe and photograph the sections under a 400x optical microscope. The results showed that the positive staining of plasminogen (green fluorescence) in muscle tissue in the drug group was significantly higher than that in the vehicle group, indicating that plasminogen can be enriched in muscle tissue. In addition, plasminogen is present in the cytoplasm (as shown in △) and the nucleus (as shown in Plasminogen and TDP-43 (red fluorescent light) in the cytoplasm (as shown by ▲) and in the nucleus (as shown by This indicates that plasminogen can be enriched in muscle tissue, enter cells, and co-localize with TDP-43 in ALS model mice. Example 7 Plasminogen promotes TDP-43 degradation in brain tissue of okadaic acid-induced dementia model mice Ten B6SJL-Tg (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas / Mmjax (FAD) female mice aged 30-32 weeks (purchased from Jackson lab, stock number: 034840) were weighed before modeling and used as the model group. Five C57 female mice aged 6-7 weeks were selected as the blank group. After grouping, the mice in the blank group and the model group were anesthetized by intraperitoneal injection of tribromoethanol, with an anesthetic dose of 20 mL / kg. The model mice were located in the basolateral amygdala according to the mouse stereotaxic atlas (according to the coordinates of the bregma: AP-1.94 mm, ML±3.15 mm, DV-4.5 mm), and each mouse was slowly microinjected bilaterally. The mice in the blank group were only drilled at the coordinate location point and no injection was performed [5]. The mice in the model group were injected with 50ng / μL okadaic acid (manufacturer: Shanghai Yuanye Biotechnology Co., Ltd., catalog number S30686-25ug:) solution, the injection rate was 0.5μL / min, the injection volume was 2μL, and after the injection, the syringe stayed for 6min and then slowly withdrew. Three days after the brain localization injection, all mice were weighed, and the model group mice were randomly divided into two groups according to their body weight, 5 mice in the drug group and 5 mice in the vehicle group. The blank group mice and the vehicle group mice were injected with 5mL / kg of the vehicle through the tail vein, and the drug group mice were injected with 50mg / k of plasminogen through the tail vein. Six hours after the single administration, the mice were killed and brain tissue was obtained. TDP-43 western blot was performed after homogenization. The results showed that the levels of TDP-43 monomer and low molecular weight TDP-43 in the brain tissue of mice in the drug-treated group were significantly lower than those in the vehicle group (Figure 8), indicating that plasminogen can promote the degradation of TDP-43 in the brain tissue of mice with dementia induced by okadaic acid. Example 8 Plasminogen promotes TDP-43 degradation in the nuclei of renal cells in amyotrophic lateral sclerosis model mice SOD1-G93A mice (Jackson Laboratory, Stock Number: 004435) and C57BL / 6J mice aged 9-10 weeks were taken. SOD1-G93A mice were randomly divided into two groups, a vehicle group and a drug-treated group, and C57BL / 6J mice were used as a normal control group, with 3 mice in each group. The mice in the vehicle group were injected with 5 mL / kg of vehicle (10 mM citric acid sodium citrate solution, pH 7.4) through the tail vein every day, and the mice in the drug-treated group were injected with 50 mg / kg of plasminogen through the tail vein every day. Normal control mice were not treated with drugs. The mice were killed after 7 days, and the kidney tissue was collected. The collected kidney tissue was placed in pre-cooled RPMI-1640 (Sigma-Aldrich) culture medium on ice. After rinsing with PBS, the kidney tissue was cut into small pieces and then incubated Digest with 0.25% pancreatin at 37°C for 10 minutes, shaking every 2 minutes. Add DMEM medium containing 10% fetal calf serum to terminate digestion. After centrifugation (1500rpm, 5 minutes), remove the supernatant and obtain a single cell pellet. Add 200μL of plasma protein extraction reagent (2×10 6 The volume of a cell pellet is about 20 μL or 40 mg) (Solarbio, R0050). Use a pipette to blow or high-speed vortex for 15 seconds to completely disperse the cell pellet into a single cell suspension. Ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, and centrifuge at 12000-16000g at 4℃ for 10 minutes. The supernatant is the extracted cytoplasmic protein. Immediately aspirate the supernatant into a pre-cooled sample tube for use. The precipitate is the cell nucleus. Completely aspirate the remaining supernatant (to avoid contamination by cytoplasmic proteins) and add 50-100 μL of nuclear protein extraction reagent. Use a pipette to blow or high-speed vortex for 15 seconds (can be extended appropriately) until the precipitate is completely dispersed, and ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, and centrifuge at 12000-16000g at 4℃ for 10 minutes. Immediately aspirate the supernatant into a pre-cooled sample tube, which is the extracted cell nuclear protein. The extracted nuclear protein was tested by western blot for TDP-43. The results showed that the level of TDP-43 in the renal cell nucleus of the drug-treated group was significantly lower than that of the vehicle group (Figure 9A-B), suggesting that plasminogen can promote the degradation of TDP-43 in the renal cell nucleus. Example 9 Plasminogen promotes TDP-43 degradation in the cytoplasm and nucleus of NSC34 cells treated with okadaic acid 10 6 NSC34 cells (Otwo Biotech, HTX1846) were seeded in 9 cm 2The cells were cultured in a culture dish with DMEM medium (Gibco, 11965092) containing 10% fetal bovine serum (EVERY GREEN, 11011-8611) and placed in a carbon dioxide incubator for culture at 37.0°C and 5% CO2. After the cells grew for 48 hours and the cell abundance reached about 80%-90%, the medium was changed and subsequent experiments were performed. The cells were divided into 4 groups: blank control group, vehicle group, drug group and drug + EACA group. The cells in the blank control group were not treated after the medium was changed; the cells in the vehicle group, drug group and drug + EACA group were exposed to okadaic acid (OA) (Shanghai yuanye Bio-Technology, S30686-25ug) at a concentration of 2.5ng / μL. After 24 hours of okadaic acid stimulation, the vehicle was added to the cell culture medium of the vehicle group, plasminogen (0.5 mg / mL) was added to the cell culture medium of the drug group, and plasminogen (final concentration was 0.5 mg / mL) and aminocaproic acid (20 mM) were added to the cell culture medium of the drug + EACA group. After adding plasminogen for another 24 hours, the cells were harvested. The culture supernatant was aspirated, washed with 1×PBS, and digested with 0.25 pancreatin 1mL for 2-3 minutes. When the cells were obviously detached, the digestion was terminated with 5-6mL of DMEM complete medium, the cells were slowly blown, the suspension was collected into a centrifuge tube, centrifuged at 1500rpm for 5min to remove the supernatant, resuspended with pre-cooled 1×PBS, and the cells were counted. 200μL of plasma protein extraction reagent (2×10 6 Cell pellet Volume is about 20μL or 40mg)(Solarbio, R0050). Use a pipette to blow or high-speed vortex for 15 seconds to make the cell pellet completely dispersed into a single cell suspension. Ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, centrifuge at 4℃12000~16000g for 10 minutes. The supernatant is the extracted cytoplasmic protein, and the supernatant is immediately aspirated into a pre-cooled sample tube for use. The precipitate is the cell nucleus, and the remaining supernatant must be completely aspirated (to avoid contamination by cytoplasmic proteins), and 50-100μL of nuclear protein extraction reagent is added. Use a pipette to blow or high-speed vortex for 15 seconds (can be extended appropriately) until the precipitate is completely dispersed, and ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, centrifuge at 4℃12000~16000g for 10 minutes. Immediately aspirate the supernatant into a pre-cooled sample tube, which is the extracted cell nuclear protein. The extracted nuclear protein was tested by western blot for TDP-43. Aminocaproic acid (EACA) is a lysine analog that blocks the high-affinity lysine binding site on plasminogen [6]. The results showed that the levels of TDP-43 in the cytoplasm and nucleus of the drug group were significantly lower than those in the nucleus of the vehicle group, and the addition of EACA could completely inhibit the effect of plasminogen on TDP-43 (Figure 10A-D), suggesting that plasminogen can degrade TDP-43 in the cytoplasm and nucleus, and this effect of plasminogen is closely related to the lysine binding site in its structure. Example 10 Plasminogen promotes the increase of plasminogen level and plasmin activity level in the cytoplasm and nucleus of NSC34 cells treated with okadaic acid 10 6 NSC34 cells (Otwo Biotech, HTX1846) were seeded in 9 cm 2 The cells were cultured in a culture dish with DMEM medium (Gibco, 11965092) containing 10% fetal bovine serum (EVERY GREEN, 11011-8611) and placed in a carbon dioxide incubator for culture at 37.0°C and 5% CO2. After the cells grew for 48 hours and the cell abundance reached about 80%-90%, the medium was changed and subsequent experiments were performed. The cells were divided into three groups: vehicle group, drug group and drug + EACA group. The cells in the vehicle group, drug group and drug + EACA group were exposed to okadaic acid (OA) (Shanghai yuanye Bio-Technology, S30686-25ug) at a concentration of 2.5ng / μL. After 24 hours of okadaic acid stimulation, the vehicle was added to the cell culture medium of the vehicle group, plasminogen (0.5 mg / mL) was added to the cell culture medium of the drug group, and plasminogen (final concentration was 0.5 mg / mL) and aminocaproic acid (20 mM) were added to the cell culture medium of the drug + EACA group. After adding plasminogen for another 24 hours, the cells were harvested. The culture supernatant was aspirated, washed with 1×PBS, and digested with 0.25 pancreatic enzyme 1mL for 2-3 minutes. When the cells were obviously detached, the digestion was terminated with 5-6mL of DMEM complete medium, the cells were blown slowly, and the suspension was collected into a centrifuge tube. The supernatant was centrifuged at 1500rpm for 5 minutes to remove the supernatant. Resuspend in pre-cooled 1×PBS and count the cells. Add 200μL of plasma protein extraction reagent to every 20μL of cell pellet. (The volume of 2×106 cell pellets is about 20μL or 40mg) (Solarbio, R0050). Use a pipette to blow or high-speed vortex for 15 seconds to completely disperse the cell pellet into a single cell suspension. Ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, centrifuge at 4℃ 12000~16000g for 10 minutes. The supernatant is the extracted cytoplasmic protein, and immediately aspirate the supernatant into a pre-cooled sample tube for use. The precipitate is the cell nucleus, and the remaining supernatant must be completely aspirated (to avoid contamination by cytoplasmic proteins), and 50-100μL of nuclear protein extraction reagent is added. Use a pipette to blow or high-speed vortex for 15 seconds (can be extended appropriately) until the precipitate is completely dispersed, and ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, centrifuge at 4℃ 12000~16000g for 10 minutes. Immediately aspirate the supernatant into a pre-cooled sample tube, which is the extracted cell nuclear protein. After cell lysis, the detection was performed according to the instructions of Human Plasminogen ELISA Kit (Manufacturer: AssayMax, Catalog No.: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard in the kit as the internal standard. The calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The activity of plasmin was detected by enzyme substrate kinetic method. 85 μL / well of standard solution at seven different concentrations, blank, and sample were added to the ELISA plate in turn, and then 15 μL of 20 mM S-2251 solution (Chromogenix, 82033239) was added to each well and incubated at 37°C. Starting from 0 min of reaction, the A405 absorbance value was read in a multifunctional ELISA reader every 5 min until the reaction was 90 min. All reactions were linearly fitted with time and absorbance, and the slope of the straight line was the reaction rate of the standard / sample (△A405 / min). Finally, the titer of the sample was calculated using the potency value of the standard and △A405 / min as a standard curve. The results showed that the levels of human plasminogen and plasmin activity in the cytoplasm and nucleus of the drug-treated group were significantly higher than those in the vehicle group, and the statistical differences were significant; the addition of EACA could completely inhibit these effects of plasminogen (Figure 11A-D), suggesting that plasminogen can enter cells and even the nucleus, increase plasmin activity, and that the entry of plasminogen into cells and nuclei is closely related to its lysine binding activity. Example 11 Administration of plasminogen promotes increase in blood plasminogen levels in SOD1-G93A mice Twenty-seven 10-15 week old B6.Cg-Tg(SOD1-G93A)1Gur / J(SOD1-G93A) mice (pedigree number: 004435) (referred to as SOD1-G93A mice) (breeding mice purchased from Jackson Laboratory, USA) were randomly divided into three groups: a vehicle control group of 3 mice, a 6 mg / kg plasminogen group of 12 mice, and a 50 mg / kg plasminogen group of 12 mice. The mice in the vehicle control group were treated with 5 ml / kg tail The vehicle was injected intravenously, and the mice in the 6mg / kg plasminogen group were injected with plasminogen (1.2mg / ml) at 6mg / kg body weight through the tail vein, and the mice in the 50mg / kg plasminogen group were injected with plasminogen (10mg / ml) at 6mg / kg body weight through the tail vein. The mice in the vehicle control group were killed 2 hours after administration, and blood was collected. Three mice in the 6mg / kg plasminogen group and the 50mg / kg plasminogen group were killed at 2, 6, 12 and 24 hours after administration, and blood was collected. After the blood was centrifuged (3500rpm, 10min, 4℃), the supernatant was taken and tested according to the instructions of the Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated with the human plasminogen working standard as the internal standard. The calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen in each sample unit total protein and perform statistical analysis. The results of plasma ELISA test of SOD1-G93A mice showed that the plasma plasminogen level of SOD1-G93A mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the plasminogen level of the 50mg / kg group was significantly higher than that of the 6mg / kg group. The plasminogen level gradually decreased 2 hours after administration and was basically metabolized within 12 to 24 hours (Figure 12). The results showed that (1) the level of plasminogen in plasma has a dose-dependent effect, and the higher the concentration of plasminogen administered, the higher the plasma plasminogen level; (2) the level of plasminogen in plasma has a time-dependent effect, first increasing and then gradually decreasing from 2 to 12 hours. Example 12 Administration of plasminogen promotes increase in plasminogen levels in brain tissue of SOD1-G93A mice Brain tissue was obtained from the mice sacrificed in Example 11, homogenized, and tested according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The human plasminogen working standard in the kit was used as the internal standard to calibrate the concentration of each sample. The calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results of ELISA level detection in the brain of SOD1-G93A mice showed that the level of plasminogen in the brain tissue of SOD1-G93A mice increased significantly after tail vein injection of 50 mg / kg and 6 mg / kg plasminogen, and the level of plasminogen in the 50 mg / kg group was significantly higher than that in the 6 mg / kg group. The level of plasminogen gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours (Figure 13A). The ratio of the level of plasminogen in brain tissue to the level of plasminogen in the blood was 3.47%, 4.94% and 6.79% 2, 6 and 12 hours after administration of plasminogen, respectively (Figure 13B). The results show that (1) under physiological and pathological conditions, the administration of plasminogen can promote the passage of plasminogen across the blood-brain barrier. (1) Plasminogen is enriched in brain tissue; (2) Intravenous injection of plasminogen into mice significantly increased the level of plasminogen in brain tissue; (3) The enrichment of plasminogen in brain tissue has a time-dependent effect, which first increases, then gradually decreases from 2 to 12 hours, and is almost completely metabolized within 12 to 24 hours; (4) The enrichment of plasminogen in brain tissue has a dose-dependent effect, and the higher the dose, the higher the level of plasminogen in brain tissue. Example 13 Administration of plasminogen promotes increase in plasminogen levels in spinal cord tissue of SOD1-G93A mice Spinal cord tissue was obtained from the mice sacrificed in Example 11, homogenized, and tested according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard in the kit as the internal standard, and the calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results of the ELISA test of the spinal cord of SOD1-G93A mice showed that the level of plasminogen in the spinal cord of SOD1-G93A mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the level of plasminogen in the 50mg / kg group was significantly higher than that in the 6mg / kg group. The level of plasminogen gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours (Figure 14). The results showed that (1) plasminogen administered at physiological dose levels could cross the blood-brain barrier of SOD1-G93A mice and accumulate in the spinal cord tissue; (2) the accumulation of plasminogen in the spinal cord was dose-dependent, and the higher the dose of plasminogen administered, the greater the accumulation; and (3) the accumulation of plasminogen in the spinal cord was time-dependent, increasing first, then gradually decreasing between 2 and 12 hours, and being essentially completely metabolized within 12 to 24 hours. Example 14 Administration of plasminogen promotes the increase of plasminogen level and plasmin activity level in brain tissue of SOD1-G93A mice Eight 22-week-old SOD1-G93A mice were randomly divided into two groups, a vehicle group and a drug-treated group, with 4 mice in each group. 2.5 mg / mL bacterial lipopolysaccharide (LPS) (Beijing Solebow Technology Co., Ltd., L8880) was administered to the vehicle group and the drug-treated group mice by tracheal instillation, with a modeling dose of 5 mg / kg. Four C57 mice of the same age were taken as normal control mice. Drug administration began 3 days after LPS treatment. The blank group mice and the vehicle group mice were injected with 5 mL / kg of the vehicle through the tail vein, and the drug-treated group mice were injected with 50 mg / k of plasminogen through the tail vein. Six hours after a single dose, the mice were killed and brain tissue was obtained. After homogenization, the plasminogen level ELISA test and the plasmin activity enzyme substrate method were performed. The results showed that the plasminogen level and plasmin activity level in the brain tissue homogenate of the mice in the drug administration group were significantly higher than those in the vehicle group, and the statistical difference was significant (Figure 15A-D), suggesting that intravenous administration of plasminogen can promote the increase of plasminogen level and plasmin activity in brain tissue. Example 15 Administration of plasminogen promotes the increase of plasminogen levels in the nuclei of brain tissue, spinal cord tissue and kidney tissue of SOD1-G93A mice Ten 9-week-old SOD1-G93A mice were randomly divided into two groups, a vehicle group and a drug group, with 5 mice in each group. Five C57 mice of the same age were taken as normal control mice. The normal group mice and the vehicle group mice were injected with 5 mL / kg of the vehicle through the tail vein, and the drug group mice were injected with 50 mg / kg of plasminogen through the tail vein every day for 7 consecutive days. After 7 days, the mice were killed to obtain brain tissue, spinal cord tissue and kidney tissue. The tissue was cut into small pieces, digested with 0.25% trypsin (Beyotime Biotechnology, C0201-500mL), and filtered with a 200-mesh cell sieve to obtain a single cell suspension. For every 20 μL of cell pellet, 200 μL of plasma protein extraction reagent (the volume of 2×106 cell pellets is about 20 μL or 40 mg) (Solarbio, R0050) was added. Use a pipette to blow or high-speed vortex for 15 seconds to make the cell pellet completely dispersed into a single cell suspension. Place in an ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, and centrifuge at 4°C 12000-16000g for 10 minutes. The supernatant is the extracted cytoplasmic protein, and it should be immediately aspirated into a pre-cooled sample tube for later use. The precipitate is the cell nucleus, and the remaining supernatant should be completely aspirated (to avoid contamination by cytoplasmic proteins), and 50-100μL of nuclear protein extraction reagent should be added. Use a pipette to blow or vortex at high speed for 15 seconds (can be extended appropriately) until the precipitate is completely dispersed, and place in an ice bath for 10 minutes. Vortex vigorously at the highest speed for 10 seconds, and centrifuge at 4°C 12000-16000g for 10 minutes. Immediately aspirate the supernatant into a pre-cooled sample tube, which is the extracted nuclear protein. The extracted nuclear protein is tested for human plasminogen level by ELISA. The results showed that 7 days after administration of plasminogen, the level of human plasminogen in the nuclei of brain tissue, spinal cord tissue and kidney tissue of SOD1-G93A mice in the administration group was significantly higher than that in the vehicle group, and the statistical difference was extremely significant (*** represents P<0.001) (Figure 16). This suggests that intravenous administration of plasminogen can promote the increase of human plasminogen levels in the nuclei of brain tissue, spinal cord tissue and kidney tissue. Example 16 Administration of plasminogen promotes increase in blood plasminogen levels in Parkinson's disease model mice Eighteen 6-week-old male C57BL / 6J mice were injected intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) solution at a rate of 35 mg / kg / mouse for 5 consecutive days to establish a Parkinson's disease model [7]. Preparation of MPTP solution: 45 mg of MPTP (Sigma, M0896) was dissolved in 9 ml of saline solution to a final concentration of 5 mg / ml. The mice were randomly divided into two groups according to their body weight, a vehicle group of 6 mice and a drug group of 12 mice. Drug administration began on day 1. The mice in the drug group were injected intravenously by tail vein. Plasminogen solution was injected into the tail vein at 50 mg / kg body weight, and the vehicle group was injected with a vehicle solution (10 mM citric acid-sodium citrate solution, pH 7.4) at 5 mL / kg body weight. Three mice in the vehicle group were killed at 2 and 24 hours after administration, and blood was collected. Mice in the drug group were killed at 2, 6, 12, and 24 hours after administration, and blood was collected. After centrifugation of the blood (3500 rpm, 10 min, 4 ° C), the supernatant was taken and tested according to the instructions of the Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard as the internal standard. The calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen in each sample per unit of total protein and statistically analyzed. The results showed that the level of plasminogen in the blood of mice in the drug administration group was significantly higher than that in the vehicle group. The level of plasminogen gradually decreased 2 hours after administration and was basically completely metabolized within 12 to 24 hours (Figure 17) (*** represents P < 0.001). Example 17 Administration of plasminogen promotes increase in plasminogen level in brain tissue of Parkinson's model mice Brain tissue was obtained from the mice sacrificed in Example 16, and after homogenization, the test was performed according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard as the internal standard, and the calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results showed that the level of plasminogen in the brain tissue of mice in the drug administration group was significantly higher than that in the vehicle group. The level of plasminogen gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours (Figure 18) (*** represents P<0.001). The results showed that plasminogen injected into the tail vein can cross the blood-brain barrier and promote the increase of plasminogen level in the brain tissue of Parkinson's model mice. Example 18 Administration of plasminogen promotes increase in plasminogen levels in spinal cord tissue of Parkinson's disease model mice Spinal cord tissue was obtained from the mice sacrificed in Example 16, and after homogenization, the test was performed according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard as the internal standard, and the calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results showed that the level of plasminogen in the spinal cord tissue of the mice in the drug group was significantly higher than that in the vehicle group. The level of plasminogen gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours (Figure 19) (** represents P < 0.01, *** represents P < 0.001). The results showed that tail vein injection The plasminogen can cross the blood-brain barrier and promote the increase of plasminogen levels in the spinal cord tissue of Parkinson's model mice. Example 19 Administration of plasminogen promotes increase in plasminogen levels in brain and spinal cord tissues of Parkinson's disease model mice Brain and spinal cord tissues were obtained from the mice sacrificed in Example 16, and after homogenization, the samples were tested according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard as the internal standard, and the calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results showed that the ratio of the level of plasminogen in spinal cord tissue to the level of plasminogen in blood was 1.24%, 1.16% and 1.46% respectively 2, 6 and 12 hours after administration of plasminogen, and the ratio of the level of plasminogen in brain tissue to the level of plasminogen in blood was 3.47%, 4.18% and 8.51% respectively 2, 6 and 12 hours after administration of plasminogen (Figure 20) (* represents P<0.05, ** represents P<0.01). The results showed that the plasminogen injected into the tail vein can cross the blood-brain barrier and promote the increase of plasminogen levels in the brain and spinal cord tissues of Parkinson's model mice. Example 20 Plasminogen promotes the increase of plasmin activity in brain tissue of Parkinson's model mice Fifteen female mice were taken and weighed before modeling. They were randomly divided into two groups according to their body weight, a blank control group of 5 mice and a model group of 10 mice. All mice in the model group were intraperitoneally injected with 5 mg / mL MPTP solution at 35 mg / kg / mouse, and no mice in the blank control group were intraperitoneally injected with 7 mL / kg normal saline. The modeling time was set at 9 am every day for 5 consecutive days. 24 hours after the last injection of MPTP, all mice were weighed and intraperitoneally injected with 5 mg / kg LPS solution. 24 hours after intraperitoneal injection of LPS, the model group mice were randomly divided into two groups according to their body weight, a drug administration group of 5 mice and a vehicle group of 5 mice. The vehicle group mice were injected with the vehicle through the tail vein, and the drug administration group mice were injected with 50 mg / kg plasminogen through the tail vein. The drugs were administered once and the samples were dissected 2 hours after administration. The brain tissue homogenate was used to detect the activity of plasmin by enzyme substrate kinetics. The activity of plasmin was detected by enzyme substrate kinetics. 85 μL / well of seven different concentrations of standard solution, blank, and sample were added to the ELISA plate in turn, and then 15 μL of 20 mM S-2251 solution (Chromogenix, 82033239) was added to each well and incubated at 37°C. Starting from 0 min of reaction, the A405 absorbance value was read in a multifunctional ELISA reader every 5 min until the reaction was 90 min. All reactions were linearly fitted with time and absorbance, and the slope of the straight line was the reaction rate of the standard / sample (△A405 / min). Finally, the titer of the sample was calculated using the titer value of the standard and △A405 / min as a standard curve. The results showed that the activity level of plasmin in the brain tissue of mice in the drug group was significantly higher than that in the vehicle group, and the statistical difference was significant (Figure 21) (* represents P<0.05). The results showed that plasminogen injected into the tail vein can cross the blood-brain barrier and promote the increase of plasmin activity in the brain tissue of Parkinson's model mice. Example 21 Administration of plasminogen promotes increase in blood plasminogen levels in Alzheimer's model mice 27 16-week-old B6SJL-Tg (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas Mmjax (Stock Number: 034840) (FAD mice for short) (breeding mice purchased from Jackson Laboratory, USA) were randomly divided into 3 groups, 3 in the vehicle control group, 12 in the 6mg / kg plasminogen group, and 12 in the 50mg / kg plasminogen group. The vehicle control group mice were injected with the vehicle at 5ml / kg of the tail vein, the 6mg / kg plasminogen group mice were injected with plasminogen (1.2mg / ml) at 6mg / kg of the body weight of the tail vein, and the 50mg / kg plasminogen group mice were injected with plasminogen (10mg / ml) at 6mg / kg of the body weight of the tail vein. The mice in the vehicle control group were killed 2 hours after administration, and blood was collected. Three mice in the 6 mg / kg plasminogen group and the 50 mg / kg plasminogen group were killed at 2, 6, 12 and 24 hours after administration, and blood was collected. After the blood was centrifuged (3500 rpm, 10 min, 4 ° C), the supernatant was taken and tested according to the instructions of the Human Plasminogen ELISA Kit (Manufacturer: AssayMax, Catalog No.: EP1200-1). The concentration of each sample was calibrated with the human plasminogen working standard as the internal standard. The calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen in each sample per unit of total protein and statistically analyzed. The results of plasma ELISA test of FAD mice showed that the plasma plasminogen level of FAD mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the plasminogen level of the 50mg / kg group was significantly higher than that of the 6mg / kg group. The plasminogen level gradually decreased 2 hours after administration and was basically metabolized completely within 12 to 24 hours (Figure 22). The results showed that (1) the level of plasminogen in plasma has a dose-dependent effect, and the higher the concentration of plasminogen administered, the more it aggregates; (2) the level of plasminogen in plasma has a time-dependent effect, first increasing and then gradually decreasing from 2 to 12 hours. Example 22 Administration of plasminogen promotes increase in plasminogen levels in brain tissue of Alzheimer's model mice Brain tissue was obtained from the mice sacrificed in Example 21, homogenized, and tested according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard as the internal standard, and the calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results of ELISA level test of FAD mouse brain showed that the plasminogen level in brain tissue of FAD mice increased significantly after tail vein injection of 50mg / kg and 6mg / kg plasminogen, and the plasminogen level in the 50mg / kg group was significantly higher than that in the 6mg / kg group. The plasminogen level gradually decreased 2 hours after administration and was basically metabolized completely in 12 to 24 hours (Figure 23A). The ratio of plasminogen in brain tissue to plasminogen in blood of mice in the 6mg / kg plasminogen group was 3.59% and 4.23% respectively after 2 and 6 hours of plasminogen injection; the ratio of plasminogen in brain tissue to plasminogen in blood of mice in the 50mg / kg plasminogen group was 2.49%, 2.31% and 3.32% respectively after 2, 6 and 12 hours of plasminogen injection (Figure 23B). The results showed that (1) under physiological and pathological conditions, administration of plasminogen promoted plasminogen to cross the blood-brain barrier and accumulate in brain tissue; (2) intravenous injection of plasminogen significantly increased the level of plasminogen in FAD mice; (3) the accumulation of plasminogen in brain tissue was time-dependent, increasing first, then gradually decreasing from 2 to 12 hours, and almost completely metabolized within 12 to 24 hours; (4) the accumulation of plasminogen in brain tissue was dose-dependent, and the higher the dose, the higher the level of plasminogen in brain tissue. Example 23 Administration of plasminogen promotes increase in plasminogen levels in brain tissue of Alzheimer's model mice Brain tissue was obtained from the mice killed in Example 21, and the enzyme substrate kinetic method of plasmin was performed after homogenization. 85 μL / well of seven different concentration points of standard solution, blank, and sample were added to the ELISA plate (manufacturer: NUNC, item number: 446469) in turn, and then 15 μL of 20mM S-2251 solution (manufacturer: Chromogenix, item number: 82033239) was added to each well and incubated at 37°C. Starting from 0 min of reaction, the A405 absorbance value was read in a multifunctional microplate reader every 5 min until the reaction was 90 min. All reactions were linearly fitted with time and absorbance, and the slope of the straight line was obtained as the reaction rate of the standard / sample (△A405 / min). Finally, the titer of the sample was calculated using the titer value of the standard and △A405 / min as a standard curve. The activity of plasmin in the total protein amount of each sample unit was calculated. The results showed that the plasminogen activity level in the brain tissue of FAD mice was significantly increased after tail vein injection of 50 mg / kg and 6 mg / kg plasminogen, and the plasminogen level in the 50 mg / kg group was significantly higher than that in the 6 mg / kg group (Figure 24). The results showed that the injection of plasminogen into mice significantly increased the level of plasmin in brain tissue. In addition, the activity of plasmin in brain tissue had a dose-dependent effect. The higher the dose, the higher the level of plasminogen in brain tissue. Example 24 Administration of plasminogen promotes increase in plasminogen levels in spinal cord tissue of Alzheimer's model mice Spinal cord tissue was obtained from the mice sacrificed in Example 21, homogenized, and tested according to the instructions of Human Plasminogen ELISA Kit (manufacturer: AssayMax, catalog number: EP1200-1). The concentration of each sample was calibrated using the human plasminogen working standard as the internal standard, and the calibrated concentration was divided by the total protein concentration to calculate the amount of plasminogen per unit of total protein in each sample and perform statistical analysis. The results of the ELISA level test on the spinal cord of FAD mice showed that the level of plasminogen in the spinal cord tissue of FAD mice increased significantly after tail vein injection of 50 mg / kg and 6 mg / kg plasminogen, and the level of plasminogen in the 50 mg / kg group was significantly higher than that in the 6 mg / kg group. The level of plasminogen gradually decreased 2 hours after administration and was basically completely metabolized within 12 to 24 hours (Figure 25A). The ratio of plasminogen in the spinal cord tissue to plasminogen in the blood of the mice in the 6 mg / kg plasminogen group was 0.93% and 1.62% 2 and 6 hours after plasminogen injection, respectively; the ratio of plasminogen in the spinal cord tissue of the mice in the 50 mg / kg plasminogen group was 0.93% and 1.62% 2, 6 and 12 hours after plasminogen injection, respectively. The ratios of plasminogen in tissue to that in blood were 0.33%, 0.40%, and 1.56%, respectively ( FIG. 25B ). The results showed that (1) the administration of plasminogen under physiological and pathological conditions can promote plasminogen to cross the blood-brain barrier and accumulate in the spinal cord tissue; (2) intravenous injection of plasminogen into mice significantly increased the level of plasminogen in the spinal cord tissue; (3) Tissue enrichment has a time-dependent effect, first increasing, then gradually decreasing from 2 to 12 hours, and almost completely metabolized within 12 to 24 hours; (4) Plasminogen enrichment in spinal cord tissue has a dose-dependent effect, and the higher the dose, the higher the level of plasminogen in the spinal cord tissue. Example 25 Plasminogen improves the condition of patients with amyotrophic lateral sclerosis This trial recruited 9 patients with amyotrophic lateral sclerosis (ALS) aged 39-60 years, including 8 patients with limb-type ALS and 1 patient with bulbar ALS, one of whom carried a FUS gene mutation. The treatment was approved by the hospital ethics committee. All patients signed informed consent. Human plasminogen lyophilized powder was dissolved in sterile water at a concentration of 5 mg / ml and administered to the patient via intravenous injection or nebulizer. The basic information of the patients and the use of plasminogen are shown in Table 1. Table 1 Basic information and plasminogen usage of ALS patients Results: Plasminogen improves motor function in ALS patients The ALS Functional Rating Scale–Revised (ALSFRS-R, ALS FRS-R) is a widely used and validated assessment tool for monitoring disability progression in ALS patients [8]. The results showed that the ALSFRS-R score of the 9 patients before administration was 20.22±10.01, which increased to 23.13±10.82 after 0.5-4 months of plasminogen administration, an increase of 4.11±5.30 points. Patient 8 is a patient with medullary ALS. After only 2 weeks of plasminogen treatment, the patient's ALSFRS-R score increased rapidly from 20 to 36. Patient 6 carries a FUS gene mutation. After 12 days of plasminogen treatment, the patient's ALSFRS-R score increased from 27 to 29. Patient 5, the patient's ALSFRS-R score dropped from 29 to 25 8 weeks after the end of the first course of treatment, but in the second course of treatment, after only 4 weeks of plasminogen nebulization treatment, the score rose to 29. In addition, in the second course of treatment, the maximum number of walking steps of patient 5 increased from more than 40 steps to more than 200 steps (Figure 26A-B). In addition, after taking plasminogen, the patient's respiratory function, writing ability, speech, swallowing, anxiety and depression, and sleep were significantly improved (Table 2). The therapeutic effects of plasminogen on ALS were compared with two existing FDA-approved drugs for the treatment of ALS, Riluzole and Edaravone. According to literature reports, after 6 months of treatment with Riluzole, the ALSFRS-R score of ALS patients decreased by -7.0±7.1 points; after 6 months of treatment with Edaravone, the ALSFRS-R score of ALS patients decreased by -5.01±0.64 points [9,10]. After 0.5 months of treatment with plasminogen, the ALSFRS-R scores of 9 ALS patients increased by 4.11±5.30 points, and no adverse events were observed during the use of plasminogen (Figure 26C and Table 3). The above results indicate that plasminogen can safely and effectively treat ALS. Table 2 Clinical phenotypes of ALS patients before and after administration of plasminogen / : indicates not observed or recorded Table 3 ALSFRS-R scores before and after treatment with plasminogen, Riluzole or Edaravone References [1]KENNETH C.ROBBINS,LOUIS SUMMARIA,DAVID ELWYN et al.Further Studies on the Purification and Characterization of Human Plasminogen and Plasmin.Journal of Biological Chemistry,1965,240(1):541-550. [2] Summaria L, Spitz F, Arzadon L et al. Isolation and characterization of the affinity chromatography forms of human Glu-and Lys-plasminogens and plasmins. J Biol Chem. 1976 Jun 25; 251(12): 3693-9. [3]HAGAN JJ, ABLONDI FB, DE RENZO EC. Purification and biochemical properties of human plasminogen. J Biol Chem. 1960Apr; 235:1005-10. [4]Porta S,Xu Y,Restrepo CR,et al.Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43pathology in vivo[J].Nature Communications,2018,9(1). [5]Kamat P K,Rai S,Nath C.Okadaic acid induced neurotoxicity:An emerging tool to study Alzheimer's disease pathology[J].Neurotoxicology,2013,37:163-172. [6]Sun Z,Chen YH,Wang P,Zhang J,Gurewich V,Zhang P,Liu JN.The blockage of the high-affinity lysine binding sites of plasminogen by EACA significantly inhibits prourokinase-induced plasminogen activation.Biochim Biophys Acta.2002Apr 29;1596(2):182-92. [7]Ding H,Underwood R,Lavalley N,et al.14-3-3inhibition promotes dopaminergic neuron loss and 14-3-3θoverexpression promotes recovery in the MPTP mouse model of Parkinson's disease[J].Neuroscience,2015,307:73-82. [8]Cedarbaum JM,Stambler N,Malta E,Fuller C,Hilt D,Thurmond B,Nakanishi A.The ALSFRS-R:a revised ALS functional rating scale that incorporates assessments of respiratory function.BDNF ALS Study Group(Phase III).J Neurol Sci.1999Oct 31;169(1-2):13-21. [9]Shibuya K,Misawa S,Kimura H et al.A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis:Efficacy and safety of sodium channel blocker phase II trial.Amyotroph Lateral Scler Frontotemporal Degener.2015;16(5-6):353-8.

[0010] Writing Group;Edaravone(MCI-186)ALS 19Study Group.Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis:a randomised,double-blind,placebo-controlled trial.Lancet Neurol.2017Jul;16(7):505-512. Sequence Listing

Claims

1. A method for promoting degradation of pathological TDP-43 protein, comprising administering to a subject a therapeutically effective amount of one or more compounds selected from the following: components of the plasminogen activation pathway, compounds that can directly activate plasminogen or indirectly activate plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.

2. The method of claim 1, wherein the component of the plasminogen activation pathway is selected from the group consisting of plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogs containing one or more kringle domains and a protease domain of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activator, tPA and uPA.

3. The method of claim 1, wherein the antagonist of the fibrinolytic inhibitor is an inhibitor of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin, such as an antibody.

4. The method of any one of claims 1 to 3, wherein the compound has one or more of the following activities: promoting the degradation of pathological TDP-43 protein in nerve tissue, promoting the degradation of pathological TDP-43 protein in muscle tissue, and promoting the degradation of TDP-43 in cells and cell nuclei.

5. A method for treating a pathological TDP-43 protein-related disease in a subject, comprising administering to the subject a therapeutically effective amount of one or more compounds selected from the following: components of the plasminogen activation pathway, compounds that can directly activate plasminogen or indirectly activate plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors, wherein the pathological TDP-43 protein-related disease is one or more selected from the following: amyotrophic lateral sclerosis (ALS), bulbar amyotrophic lateral sclerosis, Fus gene mutation amyotrophic lateral sclerosis, Alzheimer's disease, argyrophilic grain dementia, disease, ALS-parkinsonism dementia complex of Guam, vascular dementia, frontotemporal dementia (FTD), semantic dementia, dementia with Lewy bodies, Huntington's disease, Spinocere bellarataxia, inclusion body myopathy, inclusion body myositis, and Parkinson's disease.

6. The method of claim 5, wherein the component of the plasminogen activation pathway is selected from the group consisting of plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogs containing one or more kringle domains and a protease domain of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activator, tPA and uPA.

7. The method of claim 5, wherein the antagonist of the fibrinolysis inhibitor is an inhibitor of PAI-1, complement C1 inhibitor, α2 antiplasmin or α2 macroglobulin, such as an antibody.

8. The method of any one of claims 1-7, wherein the compound is plasminogen or plasmin.

9. The method of any one of claims 1-8, wherein the plasminogen is Glu-plasminogen, Lys-plasminogen, or a conservatively substituted variant thereof.

10. The method of any one of claims 1-9, wherein the plasminogen has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with sequence 2 and has lysine binding activity and / or proteolytic activity of plasminogen.

11. The method of any one of claims 1 to 10, wherein the plasminogen comprises one or more selected from the group consisting of: 1) having a serine protease domain as shown in SEQ ID NO:14; 2) a serine protease domain that is at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 14 and retains proteolytic activity; 3) Choose one from Kringle 1, Kringle 2, Kringle 3, Kringle 4 and Kringle 5 or more Kringle domains; and 4) A Kringle domain that is at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identical to one or more of Kringle 1, Kringle 2, Kringle 3, Kringle 4, and Kringle 5 and that retains lysine binding activity.

12. The method of any one of claims 1-11, wherein the plasminogen is selected from Glu-plasminogen, Lys-plasminogen, mini-plasminogen, micro-plasminogen, delta-plasminogen, or variants thereof that retain the proteolytic activity of plasminogen.

13. The method of any one of claims 1-12, wherein the plasminogen comprises the amino acid sequence shown in SEQ ID NOs: 2, 6, 8, 10, 12 or a conservatively substituted variant of the amino acid sequence shown in SEQ ID NOs: 2, 6, 8, 10, 12.

14. The method of any one of claims 1-13, wherein the plasminogen is used in combination with one or more other therapeutic approaches or drugs.

15. The method of claim 14, wherein the other treatment methods include cell therapy (including stem cell therapy), supportive therapy and physical therapy.

16. The method of any one of claims 1-15, wherein the plasminogen is administered by nasal inhalation, nebulized inhalation, nasal drops, eye drops, ear drops, intravenous, intraperitoneal, subcutaneous, sublingual, intracranial, intrathecal, intraarterial or intramuscular administration.

Images