Abstract
Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. α-Synuclein (α-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between α-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by α-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances α-syn misfolding. These data provide a direct functional connection between α-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (α-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of α-syn–induced neuron loss in animals, establishing a diverse, highly conserved interaction network for α-syn.
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Acknowledgements
We are grateful to C. Kubisch (University of Cologne) for providing the human ATP13A2 cDNA and to the Yeast Resource Center for plasmids. A.D.G. was a Lilly Fellow of the Life Sciences Research Foundation and is currently a Pew Scholar in the Biomedical Sciences. A.D.G. is also supported by the US National Institutes of Health Director's New Innovator Award Program, part of the NIH Roadmap for Medical Research, through grant number 1-DP2-OD004417-01. A.C. is supported by a postdoctoral fellowship from the Parkinson's Disease Foundation. S.L. acknowledges support from the MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research, NS038372, and the Howard Hughes Medical Institute. M.L.G. was supported by a grant from the National Parkinson Foundation. C. elegans studies in the Caldwell laboratory were supported in part by grants from the Michael J. Fox Foundation, American Parkinson Disease Foundation and Bachmann-Strauss Dystonia and Parkinson Foundation. Research in the Rochet laboratory was supported by National Institutes of Health Grant NS049221 and a grant from the American Parkinson Disease Association.
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S.L. is a founder of, a former member of the Board of Directors, and has received consulting fees from FoldRx Pharmaceuticals, a company that investigates drugs to treat protein folding diseases. A.D.G., A.A.C. and S.L. are inventors on patents and patent applications that have been licensed to FoldRx. S.L. is also a member of the Board of Directors of Johnson & Johnson. A.A.C. and J.-C. R. have received consulting fees from FoldRx Pharmaceuticals and J.-C.R. has received payment from FoldRx for testing drugs in his laboratory.
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Gitler, A., Chesi, A., Geddie, M. et al. α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41, 308–315 (2009). https://doi.org/10.1038/ng.300
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DOI: https://doi.org/10.1038/ng.300
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