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

Nature Medicine volume 8, pages 600–606 (2002)Cite this article

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.

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Figure 1: Characterization of cultured human dopaminergic neurons.
Figure 2: Neurotoxic and neuroprotective effects of α-synuclein in dopaminergic and non-dopaminergic human neurons, respectively.
Figure 3: Endogenous dopamine production is required for α-synuclein-induced apoptosis in human neurons.
Figure 4: α-Synuclein-induced apoptosis in SH-SY5Y cells requires endogenous dopamine production.
Figure 5: Neurotoxicity is mediated by soluble α-synuclein protein complexes.
Figure 6: Accumulation of soluble α-synuclein protein complexes in the substantia nigra of patients with PD.

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Acknowledgements

We thank C. Geula for assistance with dissection of human midbrain; M. Sobei for assistance with chromatography; M. Yuan for assistance with cell culture; Z. Zhang for helpful discussion; E. Masliah for providing the α-synuclein cDNA; T. Iwatsubo for providing the LB509 α-synuclein antibody; and the Harvard Brain Tissue Resource Center and University of Washington brain bank for providing postmortem human brain tissue. This work was supported by National Institutes of Health grants NS30352 and AG17573, and a Zenith Award from the Alzheimer's Association (to B.A.Y.). S.Y.K. is a fellow of the Leukemia and Lymphoma Society.

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  1. Department of Neurology, Harvard Medical School and Division of Neuroscience,The Children's Hospital, Boston, Massachusetts, USA

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

  2. Department of Pathology, University of Washington, Seattle, Washington, USA

    Lee-Way Jin

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Correspondence to Bruce A. Yankner.

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Xu, J., Kao, SY., Lee, F. et al. Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8, 600–606 (2002). https://doi.org/10.1038/nm0602-600

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