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Protein Quality Control Pathways at the Crossroad of Synucleinopathies

De Mattos, Eduardo P. ; Wentink, Anne ; Nussbaum-Krammer, Carmen ; Hansen, Christian LU ; Bergink, Steven ; Melki, Ronald and Kampinga, Harm H. (2020) In Journal of Parkinson's Disease 10(2). p.369-382
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alpha-synuclein, autophagy, molecular chaperones, protein aggregation, protein homeostasis, synucleinopathies, ubiquitin-proteasome system
in
Journal of Parkinson's Disease
volume
10
issue
2
pages
14 pages
publisher
IOS Press
external identifiers
  • scopus:85083041835
  • pmid:31985474
ISSN
1877-7171
DOI
10.3233/JPD-191790
language
English
LU publication?
yes
id
3c20e31f-0eb9-48b0-84f3-97a2fd30c2e8
date added to LUP
2020-05-11 15:43:13
date last changed
2020-05-24 06:31:52
@article{3c20e31f-0eb9-48b0-84f3-97a2fd30c2e8,
  abstract     = {<p>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.</p>},
  author       = {De Mattos, Eduardo P. and Wentink, Anne and Nussbaum-Krammer, Carmen and Hansen, Christian and Bergink, Steven and Melki, Ronald and Kampinga, Harm H.},
  issn         = {1877-7171},
  language     = {eng},
  month        = {04},
  number       = {2},
  pages        = {369--382},
  publisher    = {IOS Press},
  series       = {Journal of Parkinson's Disease},
  title        = {Protein Quality Control Pathways at the Crossroad of Synucleinopathies},
  url          = {http://dx.doi.org/10.3233/JPD-191790},
  doi          = {10.3233/JPD-191790},
  volume       = {10},
  year         = {2020},
}