Comprehensive Analysis and Experimental Validation of the Parkinson’s Disease Lysosomal Gene ACP2 and Pan-cancer

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

“…Based on the significance of mutated genes in causing inherited PD, the relevance of these interconnected compartments involved in cell clearance emerged in sporadic PD. These compartments include autophagosomes [36,38,[43][44][45][46][47], proteasome [34,48], endosomes [49,50], retromers [51,52], lysosomes [53][54][55][56][57], mitochondrial turnover [39,[58][59][60][61], and primary protein misfolding [62][63][64].…”

“…In fact, a dysfunctional membrane vesicle compartment started either in the retromer compartment of endosomes or within altered clathrin-mediated endocytosis [4,20] may be represented by engulfing multivesicular bodies (MVB). This may be added to or alternative to an early dysfunction of the autophagy machinery both at early and late stages, impeding the merging with lysosomes [30,50,[52][53][54]56,60,[116][117][118][119][120][121][122]. Still, in this scenario, a critical step involves the shuttling of the proteasome via p62 towards the nascent phagophore [123], where polyubiquitin chains interact with p62 to deliver misfolded proteins to segregated domains of degradation.…”

“…This may lead to engulfing multivesicular bodies (MVB). This may be added to or alternative to early dysfunction of the autophagy machinery (left part of the cartoon, and Figure 1) both at early and late stages, impeding the merging of the endosome/autophagosome system with lysosomes [30,50,[52][53][54]56,60,[116][117][118][119][120][121][122]. LRRK2: leucine-rich repeat kinase is altered in a genetic form of PD and it is involved in endolysosomal pathway.…”