Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1843, Issue 2, Pages 352-365Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2013.11.018
Keywords
Protein degradation; Alpha-synuclein; Proteasome; RedOx; MsrA and B; Parkinson's disease
Categories
Funding
- MINECO [SAF_2012_34556]
- Comunidad de Madrid [P2010_BMD-2331, CIBERNED]
- Fund for Scientific Research-Flanders (Belgium) [G.0156.05, G.0077.06, G.0042.07]
- Concerted Research Actions from Ghent University the Inter University Attraction Poles [BOF07/GOA/012, IUAP06]
- European Union Interaction Proteome
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Alpha-synuclein is a small protein implicated in the pathophysiology of Parkinson's disease (PD). We have investigated the mechanism of cleavage of alpha-synuclein by the 20S proteasome. Alpha-synuclein interacts with the C8 (alpha 7) subunit of the proteasome. The N-terminal part of alpha-synuclein (amino acids 1-60) is essential for its proteasomal degradation and analysis of peptides released from proteasomal digestion allows concluding that initial cleavages occur within the N-terminal region of the molecule. Aggregated alpha-synucleins are also degraded by the proteasome with a reduced rate, likely due to Met oxidation. In fact, mild oxidation of alpha-synuclein with H2O2 resulted in the inhibition of its degradation by the proteasome, mainly due to oxidation of Met I and 5 of alpha-synuclein. The inhibition was reversed by treatment of the oxidized protein with methionine sulfoxide reductases (MsrA plus MsrB). Similarly, treatment with H2O2 of N2A cells transfected with alpha-synuclein resulted in the inhibition of its degradation that was also reverted by co-transfection of MsrA plus MsrB. These results clearly indicate that oxidative stress, a common feature of PD and other synucleinopathies, promotes a RedOx change in the proteostasis of alpha-synuclein due to Met oxidation and reduced proteasomal degradation; compromised reversion of those oxidative changes would result in the accumulation of oxidative damaged alpha-synuclein likely contributing to the pathogenesis of PD. (C) 2013 Elsevier B.V. All rights reserved.
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