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.
Highlights
Accumulation of proteinaceous intraneuronal inclusions in the brain, referred to asLewy bodies (LBs), is the main neuropathological hallmark of Parkinson’s disease (PD) and related disorders [1,2]
These inclusions are mainly constituted of aggregated α-synuclein (α-syn) assembled in well-ordered fibrils [3,4,5]. α-Syn is a 140-amino acid presynaptic protein comprised of three domains: the N-terminal region (AA 1–60) which plays a role in modulating α-syn interactions with membranes; a central domain referred to as the non-Aβ component of AD amyloid (NAC) region (AA 61–95) very rich in hydrophobic amino acids essential for α-syn aggregation; and the C-terminal acidic carboxy-terminal tail (AA 96–140) implicated in regulating α-syn nuclear localization and fibrillization, as well as interactions with metals, small molecules and other proteins [1,6,7]
It has been reported that, when monomeric forms of α-syn are overexpressed, macroautophagy is inhibited through the modulation of Rab1a activity, leading to the mislocalization of autophagy-related protein 9 (Atg9), a transmembrane protein normally expressed on autophagosomes [49]
Summary
Accumulation of proteinaceous intraneuronal inclusions in the brain, referred to as. Α-syn is commonly considered as the main component of LBs, new research has reported that these abnormal proteinaceous aggregates are made of more than just accumulated insoluble proteins, but are composed of other cellular components such as cellular membrane fragments, vesicular structures, and dystrophic organelles [8,9,10] These studies have helped better refine previous findings reporting the presence of lipids and other membranous fragments within LBs [11,12,13]. Converging findings suggest that these α-syn fibrillar forms can spread in a prion-like manner through synaptically connected brain regions, leading to PD disease progression [30,31,32,33,34] This spreading might involve the vesicular system where exosomes have been proposed as the cargo for intercellular α-syn trafficking [35,36]. We will discuss work that highlights the interaction between α-syn and the main components of the endolysosomal system, in addition to dissecting recent findings on the role of these components in neuronal survival and more importantly, how α-syn impairs their function in PD
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