Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

Abstract

Abnormal accumulation of the protein α- synuclein (α-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 α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-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 α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-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.

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

“…The anti-human α-Syn antibody [69] (hSyn, green) shows that the NII does not coincide with the distribution of the residual 1B fibrils (green) that are absent in the untreated control (Ctrl. column) and that are scattered on the whole neuronal surface and in some poorly delineated perikarial regions (empty arrowheads, probably the late endolysosomal compartment [70]). This shows that the NIIs do not correspond to an accumulation of the input fibrils.…”

The relationship of alpha-synuclein to mitochondrial dynamics and quality control

“…This includes disruption to neurotransmitter release, intracellular trafficking and protein degradation amongst other processes, having a global impact on the cell that results in degeneration (Cooper et al, 2006;Sousa et al, 2009;Nemani et al, 2010). Of note, alphasynuclein oligomers have been shown to exert toxicity at mitochondria and throughout the endolysosomal system (Melo et al, 2018;Teixeira et al, 2021). Alpha-synuclein aggregates preferentially bind to mitochondria, not only reducing ATP production but also inducing fragmentation with subsequent impacts on mitophagy (Liu et al, 2009;Choubey et al, 2011;Wang et al, 2019).…”

“…Alpha-synuclein's capacity to influence both mitochondrial and endolysosomal function pathologically suggests a significant impact for alpha-synuclein oligomers on mito-QC (Melo et al, 2018;Teixeira et al, 2021). Whether this could represent a key mechanism behind alpha-synuclein-induced cellular degeneration is an important question to be addressed.…”

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

“…The researchers hypothesize that fibroblast-derived from patients harboring GBA1 mutations promote changes in the lipid composition of recipient cells, which may account for the increased phospho-α-syn, posttraductional modification that increases the formation of insolubleα-syn forms ( Canerina-Amaro et al, 2019 ). Besides releasing exosomes, MVBs can be eliminated through the ALP by a direct fusion with lysosomes or autophagosomes ( Fader et al, 2008 ; Vanlandingham and Ceresa, 2009 ; Szatmari et al, 2014 ; Teixeira et al, 2021 ). α-syn itself can disturb the ALP activity, promoting potential positive feedback to its secretion.…”