Oxidants induce alternative splicing of alpha-synuclein: Implications for Parkinson's disease.
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.
Center for Chemical Biology, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 607, India. kalivendi@iict.res.in
Shasi V
SV
Kalivendi
Deepthi
D
Yedlapudi
Cecilia J
CJ
Hillard
B
B
Kalyanaraman
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008297:Male; D008636:Mesencephalon; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D018663:Adrenergic Agents; D015259:Dopamine Agents; D016877:Oxidants; D012333:RNA, Messenger; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D012402:Rotenone; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase