Faculty Collaboration Database

Oxidants induce alternative splicing of alpha-synuclein: Implications for Parkinson's disease. Free Radic Biol Med 2010 Feb 01;48(3):377-83

Date

10/28/2009

Pubmed ID

19857570

Pubmed Central ID

PMC4485429

DOI

10.1016/j.freeradbiomed.2009.10.045

Scopus ID

2-s2.0-73449099224 (requires institutional sign-in at Scopus site)   40 Citations

Abstract

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.

Author List

Kalivendi SV, Yedlapudi D, Hillard CJ, Kalyanaraman B

Authors

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Adrenergic Agents
Alternative Splicing
Animals
Blotting, Western
Cells, Cultured
Disease Models, Animal
Dopamine Agents
Humans
Immunoblotting
Immunoenzyme Techniques
Male
Mesencephalon
Mice
Mice, Inbred C57BL
Neurons
Oxidants
Oxidopamine
Parkinson Disease
RNA, Messenger
Rats
Reverse Transcriptase Polymerase Chain Reaction
Rotenone
Substantia Nigra
Tyrosine 3-Monooxygenase
Uncoupling Agents
alpha-Synuclein