Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 48, Issue 3, Pages 377-383Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2009.10.045
Keywords
Synuclein; Parkinson's disease; Oxidative stress; Alternative splicing; Dopamine neurons; MPTP; Neurotoxicity
Funding
- DBT, India [BT/PR9787/GBD/27/73/2007]
- NIH [NS39958]
- DST, India [100/IFD/8705/2006-2007]
- UGC, India
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alpha-Synuclein (alpha-syn) is a presynaptic protein that is widely implicated in the pathophysiology of Parkinson's disease (PD). Emerging evidence indicates a strong correlation between alpha-syn aggregation and proteasomal dysfunction as one of the major pathways responsible for destruction of the dopamine neurons. Using parkinsonism mimetics (MPP+, rotenone) and related oxidants, we have identified an oxidant-induced alternative splicing of alpha-syn mRNA, generating a shorter isoform of alpha-syn with deleted exon-5 (112-syn). This spliced isoform has an altered localization and profoundly inhibits proteasomal function. The generation of 112-syn was suppressed by constitutively active MEK-1 and enhanced by inhibition of the Erk-MAP kinase pathway. Overexpression of 112-syn exacerbated cell death in a human dopaminergic cell line compared to full-length protein. Expression of 112-syn and proteasomal dysfunction were also evident in the substantia nigra and to a lesser extent in striatum, but not in the cortex of MPTP-treated mice. We conclude that oxidant-induced alternative splicing of alpha-syn plays a crucial role in the mechanism of dopamine neuron cell death and thus contributes to PD. (C) 2009 Published by Elsevier Inc.
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