α-Synuclein Trafficking in Parkinson’s Disease: Insights From Fly and Mouse Models

Abstract

Protein aggregation and accumulation are common pathological hallmarks in neurodegenerative diseases. To efficiently clear and eliminate such aggregation becomes an important cellular strategy for cell survival. Lewy bodies inclusion and aggregation of α-Synuclein (α-Syn) during the pathogenesis of Parkinson’s disease (PD) serve as a good example and are potentially linked to other pathological PD features such as progressive dopaminergic neuron cell death, behavioral defects, and nonmotor symptoms like anosmia, cognitive impairment, and depression. Years of research have revealed a variety of mechanisms underlying α-Syn aggregation, clearance, and spread. Particularly, vesicular routes associated with the trafficking of α-Syn, leading to its aggregation and accumulation, have been shown to play vital roles in PD pathogenesis. How α-Syn proteins propagate among cells in a prion-like manner, either from or to neurons and glia, via means of uptake or secretion, are questions under active investigation and have been of central interest in the field of PD study. This review covers components and pathways of possible vesicular routes involved in α-Syn trafficking. Events including but not limited to exocytosis and endocytosis will be discussed within the context of an overall cellular trafficking theme. Recent advances on α-Syn trafficking mechanisms and their significance in mediating PD pathogenesis will be thoroughly reviewed, ending with a discussion on the advantages and limitations of different animal PD models.

Characterization of Small-Molecule-Induced Changes in Parkinson's-Related Trafficking via the Nedd4 Ubiquitin Signaling Cascade

“…GO enrichment (Eden et al, 2009) shows that a-synuclein toxicity enriches ubiquitination of proteins associated with gene expression, protein synthesis, and metabolic processes relative to the total ubiquitylome (Table S3). These results are consistent with previous characterizations of processes disrupted by a-synuclein-associated ER and cellular stress (Cheng et al, 2018;Eisbach and Outeiro, 2013;Fernandes et al, 2016;Jiang et al, 2010;Lautenschl€ ager et al, 2017;Mercado et al, 2013;Zambon et al, 2019). Further analysis of ubiquitin linkage abundances (determined by comparison of diagnostic GG-K peptide abundances between samples) revealed that induction of a-synuclein toxicity increases the amount of K6-, K11-, K33-, K48-, and K63-linked ubiquitin chains relative to WT controls ( Figure 5D).…”

TRP Channels Role in Pain Associated With Neurodegenerative Diseases

“…It is proposed that oxidative stress in dopaminergic neurons prompted the activation of the p38 MAPK and c-Jun N-terminal kinase (JNK) signaling pathways that have linked to neuronal apoptosis in several models of PD (Oh et al, 2011;Sabens Liedhegner et al, 2011;Bohush et al, 2018). p38-MAPK activation has also been reported to contribute to mitophagy, a fundamental mechanism underlying α-synuclein accumulation associated with PD (Cheng et al, 2018).…”

Characterization of small molecule induced changes in Parkinson’s-related trafficking via the Nedd4 ubiquitin signaling cascade

“…These results are consistent with previous characterizations of processes disrupted by α-synuclein-associated ER and cellular stress. [39][40][41][42][43][44][45] Further analysis of ubiquitin linkage abundances (determined by comparison of diagnostic GG-K peptide abundances between samples) revealed that induction of α-synuclein toxicity increases the amount of K6, K11, K33, K48, and K63 linked ubiquitin chains relative to wild-type controls ( Figure 5D). Strikingly, K63 linkages, which primarily trigger endocytosis and lysosomal degradation of plasma membrane proteins, 46 are enriched 8-fold relative to the wild-type sample.…”