Protein Quality Control Pathways at the Crossroad of Synucleinopathies

Abstract

The pathophysiology of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and many others converge at alpha-synuclein (α-Syn) aggregation. Although it is still not entirely clear what precise biophysical processes act as triggers, cumulative evidence points towards a crucial role for protein quality control (PQC) systems in modulating α-Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating α-Syn levels. Here, we review the main aspects of α-Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone α-Syn assemblies: molecular chaperones and the ubiquitin-proteasome system and autophagy-lysosome pathway, respectively. A deeper understanding of these basic protein homeostasis mechanisms might contribute to the development of new therapeutic strategies envisioning the prevention and/or enhanced degradation of α-Syn aggregates.

Keywords: Alpha-synuclein; autophagy; molecular chaperones; protein aggregation; protein homeostasis; synucleinopathies; ubiquitin-proteasome system.

Fig. 1

Domain structure of the human alpha-synuclein (α-Syn) protein. α-Syn comprises three basic domains: an N-terminal amphipathic region, a central non-β-amyloid component (NAC) domain, and a C-terminal acidic domain. Seven membrane-interacting amino acid motifs are also present in the first half of the protein. The region preceding the NAC domain concentrates all pathogenic α-Syn mutations identified so far. Numbers on the upper part of the structure refer to amino acid positions.

Fig. 2

Targeting and processing of alpha-synuclein (α-Syn) by protein quality control (PQC) pathways. Left: in normal conditions, in which the cellular PQC capacity is in balance with the α-Syn burden, soluble as wells as pre-fibrillar α-Syn assemblies (after disassembly) have been shown to be targeted to and degraded by several PQC components. The initial survey of α-Syn species might be performed by molecular chaperones (1), which can facilitate the sorting of α-Syn to distinct degradative routes, such as the ubiquitin-proteasome system (UPS; 2), a ubiquitin-independent proteasomal degradation pathway (3), chaperone-mediated autophagy (CMA; 4), macroautophagy (5), secretion via endosomes (6) [162], and proteolytic digestion by intracellular (7) or extracellular proteases. Right: in aged organisms or pathological conditions, the α-Syn burden surpasses the cellular PQC capacity, leading to α-Syn accumulation and subsequent aggregation. Fibrillar α-Syn assemblies can trap several biomolecules, including molecular chaperones (8), which contributes to chaperone depletion and decreases PQC capacity. Similarly, α-Syn aggregation has been linked to impairment of different steps of macroautophagy (9), CMA (10), and proteasomal degradation (11). In some experimental setups, increased α-Syn levels can also lead to increased autophagic flux and destruction of organelles, such as mitochondria (12). α-Syn species can also be secreted to the extracellular space and taken up by neighboring cells (13), where they seed the aggregation of soluble α-Syn species (14). α-Syn aggregation additionally impairs the intracellular trafficking of other proteins, such as the lysosomal enzyme glucocerebrosidase (GCase; 15). Decreased lysosomal GCase activity, due to either mislocalization of wildtype (wt) GCase or mutant GCase variants (16), leads to accumulation of GCase substrates (such as glycosylceramide; 17), which might potentiate α-Syn aggregation. See main text for further mechanistic details and references. ER: endoplasmic reticulum; Hsc70: heat shock cognate 71 kDa protein; LAMP2a: lysosome-associated membrane protein 2 isoform a; poly-Ub: poly-ubiquitin.