Chimeric molecules mediating tau protein degradation based on autophagy mechanism and their applications

A chimeric molecule and protein degradation technology, applied in the fields of hybrid peptides, organic chemistry, fusion polypeptides, etc., can solve the problem that it is difficult to efficiently degrade Tau protein aggregates, etc., to overcome the inability to efficiently degrade intracellular macromolecular components. Effect

Active Publication Date: 2021-08-31
CHONGQING UNIV
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

Since phosphorylated Tau protein tends to form aggregates, it also makes it difficult for the ubiquitin-proteasome pathway to efficiently degrade Tau protein aggregates

Method used

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  • Chimeric molecules mediating tau protein degradation based on autophagy mechanism and their applications
  • Chimeric molecules mediating tau protein degradation based on autophagy mechanism and their applications
  • Chimeric molecules mediating tau protein degradation based on autophagy mechanism and their applications

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Effect test

Embodiment 1

[0037] 1. Construction of EGFP-Tau and EGFP-TauP301L fusion protein (target protein) expression vector

[0038] (1) PCR amplification of the full-length nucleic acid fragment of the Tau protein, extracting the DNA of the plasmid pET28a-Tau (containing the full sequence of the wild-type Tau protein) as an amplification template: The PCR reaction system is: 2×PCR Bestaq TM MasterMix with dye12.5μl, upstream primer Tau-F 1μl, downstream primer Tau-R 1μl, DNA template 1μl, add 9.5μl ddH 2 O to a final volume of 25 μl. Refer to Table 1 for primer sequences. The full-length nucleic acid sequence of the wild-type Tau protein is shown in SEQ ID NO:1.

[0039] Table 1. Tau protein full-length nucleic acid sequence PCR amplification primers

[0040]

[0041] The PCR reaction program was: pre-denaturation at 95°C for 5 min; denaturation at 95°C for 30 s, annealing at 58°C for 30 s, extension at 72°C for 1 min, and 32 cycles of reaction; extension at 72°C for 10 min, and the PCR pr...

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Abstract

The invention discloses a chimeric molecule that mediates the degradation of Tau protein based on an autophagy mechanism, and its amino acid sequence is shown in SEQ ID NO:5 or 7. Also disclosed is a nucleic acid molecule encoding the chimeric molecule that mediates Tau protein degradation based on an autophagy mechanism; an expression vector comprising the nucleic acid molecule. Also disclosed are the applications of the chimeric molecules, nucleic acid molecules and expression vectors that mediate Tau protein degradation based on autophagy mechanism in degrading Tau protein. The invention develops a novel targeting chimeric molecule, which is combined on the surface of the aggregation protein Tau, thereby recruiting the Tau protein into the cell autophagosome and promoting its degradation through the cell autophagy pathway. The new protein targeted degradation technology provided by the present invention is expected to apply this new technology to different target proteins, thereby overcoming the inability of the current protein targeted degradation technology based on the ubiquitin-proteasome pathway to efficiently degrade intracellular macromolecules point defects.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to a chimeric molecule that mediates the degradation of Tau protein based on an autophagy mechanism and its application. Background technique [0002] Neurodegenerative diseases are a general term for a group of diseases characterized by the progressive loss of central neurons, and have attracted much attention because of their undruggability and serious impact on the quality of life of middle-aged and elderly patients. These include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Studies have shown that the occurrence of most neurodegenerative diseases is accompanied by the abnormal accumulation of aggregates formed by misfolded proteins in nerve cells, which can have toxic effects on neurons. [0003] For this type of disease, currently clinically, small molecule inhibitors are mainly used to bind to the active si...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00C12N15/62C12N15/85C12N5/10C07K1/12
CPCC07K1/12C07K14/4702C07K2319/00C12N15/85
Inventor 杨爱民梅礼刚林昌海
Owner CHONGQING UNIV
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