Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity.
Mutations of the alpha-synuclein gene have been identified in autosomal dominant Parkinson's disease (PD). Transgenic mice overexpressing wild-type human alpha-synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum. To study the mechanism of action through which mutant alpha-synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) alpha-synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant alpha-synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha-synuclein induced a significant increase in sensitivity to dopamine toxicity compared with the wild-type protein expression. These results provide an explanation for the preferential dopaminergic neuronal degeneration seen in both the PD G209A mutant alpha-synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.
Tabrizi
S J
SJ
University Department of Clinical Neurosciences, Royal Free and University College Medical School, London NW3 2PF, UK.
Orth
M
M
Wilkinson
J M
JM
Taanman
J W
JW
Warner
T T
TT
Cooper
J M
JM
Schapira
A H
AH
D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology*; D064420:Drug-Related Side Effects and Adverse Reactions; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004441:Ecdysterone; C008999:ponasterone A; D004298:Dopamine