| abstract |
The pharmacokinetics and key technologies of the present invention are summarized in Fig. Specifically, malignant degenerative proteins such as mutant huntingtin and alpha-synuclein are clumped together and grow into oligomeric solid (①, ②), fibrillar haploid (③), and ultimately encapsulation body (④). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation (⑤) of vesicle chaperones such as BiP, and then argininated BiP (R-BiP) exits the cytoplasm and binds to the denatured protein (6). The Nt-Arg of R-BiP binds to the ZZ domain of p62 as a ligand (⑦) and the normally inactivated form of p62 is changed to an open form, thereby inducing structural activation (⑧). Thus, PB1 and LC3- Lt; / RTI > Based on the oligomerization (⑨) by the PB1 domain, it binds to the denatured protein coagulant and concentrates into a coagulant capable of autophagy degradation, ie, the p62 body (10). The p62 then binds to LC3, which is protruding from the autopagosomal membrane, to complete autophagy targeting (⑪) and lysosomal proteolysis. In young neurons, the cytotoxic protein coagulant (①-⑤) is not accumulated due to the strong decomposition of autophagy protein composed of ⑤-⑪, but the aged nerve cell is weakened by decomposition of autophagic protein in step ⑤-⑪, The solid (①-⑤) accumulates and falls into a vicious cycle. In the present invention, p62 is artificially activated (⑫, ⑬) by using a low mass ligand of p62 ZZ domain to effectively remove Huntington's and alpha-synuclein protein coagulants. Specifically, p62, which is ligated with a ligand through step (12), is intended to promote p62-R-BiP-denatured protein oligomerization (9) and autophagy solidification (10). In addition, through step (13), the ligand-p62 complex acts as an autophagy activator (14) to promote autophagosomal formation by promoting the synthesis of LC3 and the conversion of LC3-I to LC3-II. |