Abstract
Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body–confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.
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Acknowledgements
This study was supported by the American Parkinson's Disease Association, the US National Institutes of Health (NS074366, NS37167, NS078287, NS094564, AG10133, AG043970 and NS095972), the National Natural Science Foundation of China (81271921, 81430023 and 81471300), the Les Turner ALS Foundation/Herbert and Florence C. Wenske Foundation Professorship, the George Link Jr. Foundation, the Les Turner ALS Foundation and the Foglia Family Foundation. Whole-exome sequencing was performed at the John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine. Imaging work was performed at the Northwestern University Cell Image Facility supported by the National Institutes of Health (CA060553).
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H.-X.D., A.H.R. and T.S. designed this study. H.-X.D., Y.S., Y.Y., K.B.A., M.A.P.-V. and T.S. performed linkage analysis. H.-X.D., Y.S., Y.Y., K.B.A., C.H., H.Z., S.D., K.N., H.D., B.T., Z.Y., Y.X., P.C., B.H., Z.S., Z.L., J.M.V. and T.S. performed sequencing analysis. H.-X.D., Y.S., N.M., L.C., H.Z., F.F. and Y.-C.M. performed cell culture, immunoblotting, immunohistochemistry and confocal microscopy. N.M. and Y.-C.M. performed primary neuron culture and the trafficking assay. M.J.K. and D.K. performed the SNCA degradation assay. N.J.C. and D.A.N. performed immunogold electron microscopy. N.S. and A.H.R. collected family information and coordinated this study. B.T., Y.X., P.C., X.-P.G., Z.S., Z.L., J.J., J.M.V., O.M., A.H.R. and T.S. performed clinical studies. T.F., B.G. and A.H.R. performed pathological study and provided pathological samples. H.-X.D., A.H.R. and T.S. analyzed the data and wrote the manuscript.
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Deng, HX., Shi, Y., Yang, Y. et al. Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet 48, 733–739 (2016). https://doi.org/10.1038/ng.3589
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DOI: https://doi.org/10.1038/ng.3589
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