Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease.
The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54 83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.
Xu
Jin
J
Department of Neurology, Harvard Medical School and Division of Neuroscience,The Children's Hospital, Boston, Massachusetts, USA.
Kao
Shyan-Yuan
SY
Lee
Frank J S
FJ
Song
Weihong
W
Jin
Lee-Way
LW
Yankner
Bruce A
BA
D048948:14-3-3 Proteins; D017209:Apoptosis; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D013378:Substantia Nigra / Q000473:pathology; D051843:Synucleins; D014162:Transfection; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000502:physiology; D051844:alpha-Synuclein
D048948:14-3-3 Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010750:Phosphoproteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine