Prevention and treatment of neurodegenerative diseases through autophagy activity mediated by a synthetic ligand or arginylated BIP binding to the P62 ZZ domain

摘要

The pharmacokinetics and key technologies of the present invention are summarized in FIG. 1. Particularly, malignant misfolded proteins such as mutant huntingtin and alpha-synuclein are coagulated and grow into oligomeric coagulum ({circle around (1)}, {circle around (2)}, fibrillar coagulum ({circle around (3)}) and eventually inclusion body ({circle around (4)}). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation ({circle around (5)}) of vesicle chaperones such as BiP secreted into the cytoplasm, and then arginylated BiP (R-BiP) is secreted binds to the misfolded proteins ({circle around (6)}). As a ligand, the Nt-Arg of R-BiP binds to the p62 ZZ domain ({circle around (7)}), and the normally inactivated closed form of p62 is changed to an open form, leading to structural activation ({circle around (8)}). As a result, PB1 and LC3-binding domains are exposed. The PB1 domain induces oligomerization ({circle around (9)}), leading to the concentration as a p62 body ({circle around (10)}) that is a coagulum capable of being degraded by autophagy. Then, p62 binds to LC3, which is protruding from the autopagosomal membranes, leading to the completion of autophagy targeting ({circle around (11)}) and lysosomal proteolysis. Since autophagy proteolysis including steps ({circle around (5)})-({circle around (11)}) is strong in young neurons, cytotoxic protein coagulums ({circle around (1)}-{circle around (5)}) do not accumulate. However in aged neurons, autophagy proteolysis including steps {circle around (5)}-{circle around (11)} is weakened, and protein coagulums ({circle around (1)}-{circle around (5)}) accumulate and become cytotoxic. In this invention, p62 is intentionally activated ({circle around (12)}, {circle around (13)}) by using low mass ligands of the p62 ZZ domain to effectively remove huntingtin and alpha-synuclein protein coagulums. Particularly, in step {circle around (12)}, p62 ligated with a ligand accelerates the oligomerization of p62-R-BiP-misfolded protein ({circle around (9)}) and the formation of autophagy coagulum ({circle around (10)}). In step ({circle around (13)}), the ligand-p62 conjugate acts as an autophagy activator ({circle around (14)}) to induce the synthesis of LC3 and the conversion of LC3-I into LC3-II in order to accelerate the formation of autophagosomes ({circle around (15)}).