کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1909579 | 1046731 | 2010 | 7 صفحه PDF | دانلود رایگان |
α-Synuclein (α-syn) is a presynaptic protein that is widely implicated in the pathophysiology of Parkinson's disease (PD). Emerging evidence indicates a strong correlation between α-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 α-syn mRNA, generating a shorter isoform of α-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 α-syn plays a crucial role in the mechanism of dopamine neuron cell death and thus contributes to PD.
Journal: Free Radical Biology and Medicine - Volume 48, Issue 3, 1 February 2010, Pages 377–383