Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson disease

Jin Xu, Shyan Yuan Kao, Frank J S Lee, Weihong Song, Lee-Way Jin, Bruce A. Yankner

Research output: Contribution to journalArticle

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Abstract

The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of α-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, α-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 α-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble α-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.

Original languageEnglish (US)
Pages (from-to)600-606
Number of pages7
JournalNature Medicine
Volume8
Issue number6
DOIs
StatePublished - 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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