Alpha-Synuclein And The Endolysosomal System In Parkinson'S Disease: Guilty By Association

Abnormal accumulation of the protein alpha- synuclein (alpha-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson's disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between alpha-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between alpha-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated alpha-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing alpha-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of alpha-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.