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