Protein Quality Control Pathways at the Crossroad of Synucleinopathies

Eduardo P De Mattos, Anne Wentink, Carmen Nussbaum-Krammer, Christian Hansen, Steven Bergink, Ronald Melki, Harm H Kampinga*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

3 Citations (Scopus)
80 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)369-382
Number of pages14
JournalJournal of Parkinson's Disease
Volume10
Issue number2
Early online date24-Jan-2020
DOIs
Publication statusPublished - 3-Apr-2020

Keywords

  • Alpha-synuclein
  • synucleinopathies
  • protein homeostasis
  • protein aggregation
  • molecular chaperones
  • ubiquitin-proteasome system
  • autophagy
  • MUTANT ALPHA-SYNUCLEIN
  • CHAPERONE-MEDIATED AUTOPHAGY
  • MULTIPLE SYSTEM ATROPHY
  • GLIAL CYTOPLASMIC INCLUSIONS
  • HEAT-SHOCK PROTEINS
  • PARKINSONS-DISEASE
  • FIBRIL FORMATION
  • IMPAIRS MACROAUTOPHAGY
  • LYSOSOMAL DEGRADATION
  • MOLECULAR CHAPERONES

Cite this