Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome
- PMID: 18715677
- DOI: 10.1016/j.neurobiolaging.2008.07.008
Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome
Abstract
Proteasomal dysfunction may play a role in neurodegenerative conditions and protein aggregation. Overexpression in neuronal cells of alpha-synuclein, a molecule linked to Parkinson's Disease, may lead to proteasomal dysfunction. Using PC12 cells stably expressing wild-type or mutant alpha-synuclein and gel filtration, we demonstrate that soluble, intermediate size oligomers of alpha-synuclein co-elute with the 26S proteasome. These soluble oligomers associate with the 26S proteasome and are significantly increased following treatment with proteasomal, but not lysosomal, inhibitors, indicating specific degradation of these particular species by the 26S proteasome. Importantly, expression of alpha-synuclein resulted in a significant inhibition of all proteasomal activities without affecting the levels or assembly of the 26S proteasome. Pharmacological dissociation of alpha-synuclein oligomers restored proteasomal function and reduced polyubiquitinated protein load in intact cells. Our findings suggest a model where only a subset of specific soluble cell-derived alpha-synuclein oligomers is targeted to the 26S proteasome for degradation, and simultaneously inhibit its function, likely by impeding access of other proteasomal substrates.
Copyright 2008 Elsevier Inc. All rights reserved.
Similar articles
-
Proteasomal inhibition hypersensitizes differentiated neuroblastoma cells to oxidative damage.Neurosci Lett. 2006 May 15;399(1-2):27-32. doi: 10.1016/j.neulet.2005.09.086. Epub 2006 Apr 11. Neurosci Lett. 2006. PMID: 16584840
-
Endogenous catecholamine enhances the dysfunction of unfolded protein response and alpha-synuclein oligomerization in PC12 cells overexpressing human alpha-synuclein.Neurosci Res. 2010 Jan;66(1):124-30. doi: 10.1016/j.neures.2009.10.005. Epub 2009 Oct 14. Neurosci Res. 2010. PMID: 19835916
-
PA700, the regulatory complex of the 26S proteasome, interferes with alpha-synuclein assembly.FEBS J. 2005 Aug;272(16):4023-33. doi: 10.1111/j.1742-4658.2005.04776.x. FEBS J. 2005. PMID: 16098186
-
Inhibition of lysosomal functions reduces proteasomal activity.Neurosci Lett. 2009 May 29;456(1):15-9. doi: 10.1016/j.neulet.2009.03.085. Epub 2009 Mar 31. Neurosci Lett. 2009. PMID: 19429125
-
Role of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance.Mol Neurobiol. 2022 Sep;59(9):5379-5407. doi: 10.1007/s12035-022-02897-1. Epub 2022 Jun 14. Mol Neurobiol. 2022. PMID: 35699874 Review.
Cited by
-
A novel "molecular tweezer" inhibitor of α-synuclein neurotoxicity in vitro and in vivo.Neurotherapeutics. 2012 Apr;9(2):464-76. doi: 10.1007/s13311-012-0105-1. Neurotherapeutics. 2012. PMID: 22373667 Free PMC article.
-
Molecular chaperones in Parkinson's disease--present and future.J Parkinsons Dis. 2011;1(4):299-320. J Parkinsons Dis. 2011. PMID: 22279517 Free PMC article. Review.
-
Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies.Cells. 2021 Feb 12;10(2):375. doi: 10.3390/cells10020375. Cells. 2021. PMID: 33673034 Free PMC article. Review.
-
Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models.Autophagy. 2022 Sep;18(9):2104-2133. doi: 10.1080/15548627.2021.2016256. Epub 2022 Jan 9. Autophagy. 2022. PMID: 35000546 Free PMC article.
-
Human pericytes degrade diverse α-synuclein aggregates.PLoS One. 2022 Nov 18;17(11):e0277658. doi: 10.1371/journal.pone.0277658. eCollection 2022. PLoS One. 2022. PMID: 36399706 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
