The role of the endolysosomal pathway in α-synuclein pathogenesis in Parkinson's disease

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative disease that is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain (SNpc). Extensive studies into genetic and cellular models of PD implicate protein trafficking as a prominent contributor to the death of these dopaminergic neurons. Considerable evidence also suggests the involvement of α-synuclein as a central component of the characteristic cell death in PD and it is a major structural constituent of proteinaceous inclusion bodies (Lewy bodies; LB). α-synuclein research has been a vital part of PD research in recent years, with newly discovered evidence suggesting that α-synuclein can propagate through the brain via prion-like mechanisms. Healthy cells can internalize toxic α-synuclein species and seed endogenous α-synuclein to form large, pathogenic aggregates and form LBs. A better understanding of how α-synuclein can propagate, enter and be cleared from the cell is vital for therapeutic strategies.

Keywords: Parkinson’s disease; endocytosis; endolysosomal; trafficking; α-synuclein.

FIGURE 1

Cellular pathways implicated in PD pathogenesis. Genetic studies of heritable PD have highlighted vital pathways that can contribute to the pathogenesis of PD. Organelle dysfunction within the neuron, due to many genetic and environmental factors, can lead to cellular stress and eventual neuronal death. Major pathways outline here implicate protein trafficking, endolysosomal dysfunction, autophagy lysosomal pathway and mitochondrial function as vital in PD pathogenesis. Biorender image (adapted from Polymeropoulos et al., 1997; Zimprich et al., 2011; Krebs et al., 2013; Macleod et al., 2013; Vilariño-Güell et al., 2013; Cilia et al., 2014; Fonseca et al., 2015; Ferreira and Gahl, 2017).

FIGURE 2

α-synuclein aggregation model. α-synuclein exists as natively unfolded monomers that can reversibly form dimers, tetramers, and oligomeric species. α-synuclein has the propensity to aggregate irreversibly into β-rich fibrils which are the primary component of Lewy bodies.

FIGURE 3

Diagram of uptake, trafficking and clearance mechanisms of α-synuclein in the cell. There are four primary routes of uptake of α-synuclein into the cell: clathrin-mediated, LAG3 receptor-mediated, heparan sulfate proteoglycans-mediated, and passive diffusion. Different conformations of α-synuclein can be internalized via different routes. The autophagolysosomal pathway and the ubiquitin proteasome pathway are the primary clearance mechanisms that degrade α-synuclein. The autophagolysosome pathway can degrade larger species of α-synuclein, where the proteosome breaks down monomers and small, soluble oligomers.