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 (␣-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 ␣-Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating ␣-Syn levels. Here, we review the main aspects of ␣-Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone ␣-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 ␣-Syn aggregates.

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

“…Accumulating evidence indicate a role of TOR1A in the cellular protein quality control system in which TOR1A could be both substrate and effector [18]. In the 264 genome variants, we observed six variants in five genes, CHGB, DOP1B, MTMR6, P2RY13 and PPP1R15A, that are annotated with protein synthesis and transport functions (Table 4) triggers endoplasmic reticulum stress response [74,75]. In the TOR1A ΔE mutation background, we identified six candidate modifier genome variants in five genes that have known functions in endoplasmic reticulum for protein post translational modification, protein translocation and endoplasmic reticulum stress response (Table 4).…”

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

“…TorsinA functions to protect against insults from protein aggregates in the neural system (G. Beauvais et al, 2016). Protein aggregates are products of protein misfolding commonly seen in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prion disease, which triggers endoplasmic reticulum stress response (De Mattos et al, 2020; Scheper & Hoozemans, 2015). In the TOR1A ΔE mutation background, we identified six candidate modifier genome variants in five genes that have known functions in endoplasmic reticulum for protein post translational modification, protein translocation and ER stress response (Table 4).…”

Crosstalk Between Alpha-Synuclein and Other Human and Non-Human Amyloidogenic Proteins: Consequences for Amyloid Formation in Parkinson’s Disease

“…In accord with the key role of aS in PD, duplications, triplications and point-mutations in the aS gene, enhancing concentration and aggregation propensity, are linked to familial PD cases [8]. It is thought that aS assembly to amyloid fibers via intermediate oligomers results in toxic gain-of-functions, that are coupled to mitochondrial dysfunction, oxidative stress, protein degradation failure, and eventually cell death [9]. Soluble aS oligomers have been proposed to be most toxic [10,11], but work with pre-formed ␣S fibrils have demonstrated that the amyloid fibrils themselves are toxic and can be transmitted from cell to cell and are also able to cross the blood-brain barrier [12][13][14].…”

“…The NAC region (residues 61-94) is hydrophobic and contains several amino-acid repeats which constitute the core of the amyloid structures formed upon aS aggregation. Most PD cases are sporadic, but there are disease-causing mutations, all found in the N-terminal part (A30P, E46K, H50Q, G51D, A53T/E/V), that promote early-onset PD [9]. aS is acetylated at the N-terminus in vivo [26] and posttranslational modifications such as phosphorylation, ubiquitination, and C-terminal truncations are found in aS aggregate deposits [9].…”