The
drug action mechanisms and core techniques of the present invention are summarized in figure 1. Specifically, the invention provides malignant denatured proteins, such as
mutant Huntingtin proteinor alpha-
synuclein, stick together to grow into
oligomer aggregates (1, 2), fibrillar aggregates (3), and ultimately
inclusion bodies (4). Young neuronal cells produce a large quantity of Nt-Arg through N-terminal arginylation (5) of
endoplasmic reticulum chaperones, such as BiP, and thereafter, arginylated BiP (R-BiP) comes into the
cytoplasm and binds with denatured proteins (6). Nt-Arg of R-BiP, as a ligand, binds with the ZZ domain of p62 (7) to induce the structural activation of p62 (8) while the ordinarily closed inactive form of p62 is changed with an
open form thereof, and thus PB1 and LC3-binding domains are exposed. On the basis of oligomerization (9) by the PB1 domain, p62 binds with the denatured
protein aggregates to be concentrated to autophagically degradable aggregates, that is, p62 bodies (10). Thereafter, p62 completes
autophagy targeting (11) and lysosomal
proteolysis through binding with LC3 protruding on the autophagosomal membranes. In young neuronal cells, theautophagic
proteolysis occurring through steps 5-11 is strong, and thus the cytotoxic
protein aggregates (1-5) do not accumulate, but in aged neuronal cells, the autophagic
proteolysis occurring through steps 5-11 is weakened, and thus the
protein aggregates (1-5) accumulate, resulting in a vicious cycle. The present invention attempts to effectively remove
Huntingtin and alpha-
synuclein protein aggregates and the like by artificially activating p62 using low-
mass ligands of the p62 ZZ domain (12, 13). Specifically, p62 binding the ligands through step 12 promotes p62-R-BiP-denatured protein oligomerization (9) and
autophagy aggregate formation (10). In addition, the ligand-62 conjugates step 13 act as
autophagy activators (14), to promote LC3 synthesis, the conversion of LC3-I into LC3-II, and the like, thereby promoting the formation of autophagosomes (15).