Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein.
Linkage of alpha-synuclein (alpha-SN) mutations to familial Parkinson's disease (PD) and presence of alpha-SN as a major constituent of Lewy body in both sporadic and familial PD implicate alpha-SN abnormality in PD pathogenesis. Here we demonstrate that overexpression of wild-type or mutant alpha-SN does not cause any deleterious effect on the growth or continued propagation of transfected human cells, but overproduction of mutant alpha-SN heightens their sensitivity to menadione-induced oxidative injury. Such enhanced vulnerability is more pronounced in neuronal transfectants than in their nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated alpha-SN, especially with an alanine-to-proline substitution at residue 30, sensitizes neuronal cells to oxidative damage.
Ko
L
L
Department of Pharmacology, Mayo Clinic, Jacksonville, Florida 32224, USA.
Mehta
N D
ND
Farrer
M
M
Easson
C
C
Hussey
J
J
Yen
S
S
Hardy
J
J
Yen
S H
SH
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D051843:Synucleins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D014812:Vitamin K / Q000494:pharmacology; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C497604:SNCA protein, human; D013438:Sulfhydryl Compounds; D051843:Synucleins; D013778:Tetrazolium Salts; D013844:Thiazoles; D051844:alpha-Synuclein; D014812:Vitamin K; C022616:thiazolyl blue