Novel therapeutic target PRMT3 for Tau proteopathy

Abstract

The invention discloses a novel Tau proteopathy treatment target PRMT3, and relates to the technical field of Tau proteopathy treatment, the key points of the technical scheme are as follows: the target PRMT3 is used for promoting asymmetric dimethylation of histone H4R3, and the action flow of the target PRMT3 is as follows: methylated H4R3me2a is combined with a promoter region of miR-448 to promote transcription of miR-448, so that the target PRMT3 is obtained. Meanwhile, excessive miR-448 is combined with mRNA of IGF1R through complementary base pairing, so that the mRNA of the IGF1R is degraded, a PI3K / AKT / GSK3beta signal axis is further inhibited, and the phosphorylation level of Tau is promoted. According to the application, PRMT3 is taken as a therapeutic target, Tau pathological changes can be effectively relieved by knocking down the expression level of PRMT3 or using an inhibitor to reduce the activity of PRMT3 protein, and the neuronal function and the cognitive function are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of Tau disease treatment, and more specifically, to a new Tau disease treatment target PRMT3. Background Art

[0002] Tauopathies are a class of neurodegenerative diseases with high clinical and pathological heterogeneity, including primary tauopathies such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease, frontotemporal dementia (FTD) and primary aging-related tauopathies (PART), as well as secondary tauopathies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE); the pathological characteristics of these diseases are abnormal aggregation of hyperphosphorylated tau proteins. Despite their different clinical manifestations, they may be interconnected and affect disease manifestations through common underlying mechanisms; as tau pathology is a key common mechanism, tau has become an important target for the development of therapeutic strategies.

[0003] Currently, antibody therapy targeting Tau protein has been the focus of most clinical trials; however, because Tau is an endogenous protein, there may be a risk of adverse or even irreversible autoimmune reactions; identifying the upstream drivers of Tau hyperphosphorylation and targeting them with small molecule inhibitors is a promising clinical approach.

[0004] Current research mainly focuses on the phosphokinase GSK3β that catalyzes Tau phosphorylation; however, GSK3β downstream involves multiple physiological pathways, including glucose metabolism, cell proliferation and apoptosis, and its inhibition may lead to a wide range of non-target effects; at the same time, targeting the upstream regulatory mechanism of Tau hyperphosphorylation, such as specific molecular switches or epigenetic regulatory factors, may provide a more specific way to restore Tau homeostasis than directly inhibiting downstream kinases, and may have fewer side effects. Therefore, the present invention provides a new therapeutic target PRMT3 for Tau protein disease. Summary of the invention

[0005] The purpose of the present invention is to provide a new therapeutic target PRMT3 for Tau disease. The present invention takes PRMT3 as a therapeutic target, and can effectively alleviate Tau pathological changes and improve neuronal function and cognitive function by knocking down PRMT3 protein levels or using inhibitors to reduce PRMT3 protein activity.

[0006] The above technical purpose of the present invention is achieved through the following technical scheme: a new therapeutic target PRMT3 for Tau protein disease, wherein the target PRMT3 is used to promote the asymmetric dimethylation of histone H4R3.

[0007] The present invention is further configured as follows: the action process of the target PRMT3 is:

[0008] Methylated H4R3me2a binds to the promoter region of miR-448, promoting the transcription of miR-448. At the same time, excessive miR-448 binds to IGF1R mRNA through base complementary pairing, leading to IGF1R mRNA degradation, further inhibiting the PI3K / AKT / GSK3β signaling axis and promoting the phosphorylation level of Tau.

[0009] The present invention also provides a small molecule inhibitor, which is used to inhibit the activity of PRMT3 as claimed in claim 1 or 2.

[0010] The present invention also provides a pharmaceutical composition, comprising the small molecule inhibitor according to claim 3 and at least one drug carrier.

[0011] The present invention also provides an application of a small molecule inhibitor in treating Tau protein disease.

[0012] The present invention also provides an application of a small molecule inhibitor in the preparation of a drug for treating Tau protein disease.

[0013] The present invention also provides an application of a small molecule inhibitor in improving the neuronal function and cognitive function of patients with Tau protein disease.

[0014] In summary, the present invention has the following beneficial effects:

[0015] 1. The present invention can effectively reduce the phosphorylation level of Tau protein by knocking down the expression level of PRMT3 protein or using a small molecule inhibitor of PRMT3, which is one of the key factors in the pathological changes of Tau protein. Reducing the phosphorylation level helps to reduce the abnormal excessive aggregation of Tau protein, thereby slowing down the progression of neurodegenerative diseases;

[0016] 2. The small molecule inhibitors of the therapeutic target PRMT3 in the present invention can improve the function of neuronal cell models, which is crucial for the treatment of neurodegenerative diseases. By restoring the normal function of neurons, the progression of the disease can be delayed and the symptoms of patients can be improved;

[0017] 3. The present invention can more specifically affect the phosphorylation of Tau protein by targeting PRMT3, reduce non-target effects, and thus may have fewer side effects;

[0018] 4. In the present invention, the therapeutic target PRMT3 is used as an upstream regulatory factor of Tau protein phosphorylation, and has the potential to be used as a therapeutic target for a wide spectrum of Tau diseases, which means that it may have a therapeutic effect on a variety of Tau diseases. DETAILED DESCRIPTION

[0019] The present invention is described in further detail below.

[0020] Example 1: A new therapeutic target PRMT3 for Tau disease. The target PRMT3 is used to promote asymmetric dimethylation of histone H4R3. The action process of the target PRMT3 is as follows: it binds to the promoter region of miR-448 through methylated H4R3me2a to promote the transcription of miR-448. At the same time, excessive miR-448 binds to IGF1R mRNA through base complementary pairing, resulting in IGF1R mRNA degradation, further inhibiting the PI3K / AKT / GSK3β signaling axis and promoting the phosphorylation level of Tau.

[0021] Example 2: A small molecule inhibitor for inhibiting the activity of the therapeutic target PRMT3 as in Example 1.

[0022] In this example, a 20 mg / kg dose of the PRMT3 small molecule inhibitor SGC707 was used to inhibit the protein activity of PRMT3 in the brain of PS19 mice (a model mouse with hyperphosphorylated Tau protein) by intraperitoneal injection, and the drug was administered every other day for 2 months. The cognitive ability of mice was detected using water maze experiments and Y maze experiments. The results showed that inhibiting PRMT3 protein activity can significantly improve the cognitive ability of PS19 model mice; therefore, PRMT3, as an upstream regulator of Tau protein phosphorylation, has the potential to be a therapeutic target for broad-spectrum Tau protein diseases.

[0023] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A novel therapeutic target for tauopathy, PRMT3, characterized by: The target PRMT3 is used to promote asymmetric dimethylation of histone H4R3.

2. A novel therapeutic target PRMT3 for Tau disease according to claim 1, characterized in that: The action process of the target PRMT3 is as follows: Methylated H4R3me2a binds to the promoter region of miR-448, promoting the transcription of miR-448. At the same time, excessive miR-448 binds to IGF1R mRNA through base complementary pairing, leading to IGF1R mRNA degradation, further inhibiting the PI3K / AKT / GSK3β signaling axis and promoting the phosphorylation level of Tau.

3. A small molecule inhibitor characterized by: The small molecule inhibitor is used to inhibit the activity of PRMT3 as claimed in claim 1 or 2.

4. A pharmaceutical composition, characterized in that: The composition comprises the small molecule inhibitor according to claim 3 and at least one drug carrier.

5. Use of a small molecule inhibitor according to claim 3 in treating Tau disease.

6. Use of a small molecule inhibitor according to claim 3 in the preparation of a drug for treating Tau disease.

7. Use of a small molecule inhibitor according to claim 3 in improving neuronal function and cognitive function in patients with Tauopathy.