Funding agencies: This work was supported by the Royal Free Peter Samuel fund, the Wellcome Trust/MRC joint call in Neurodegeneration award (WT089698), the Kattan Trust for Parkinson's Disease Research, and Parkinson's UK (Innovation Grant K-1111).
Somatic alpha-synuclein mutations in Parkinson's disease: Hypothesis and preliminary data
Article first published online: 14 MAY 2013
© 2013 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 28, Issue 6, pages 705–712, June 2013
How to Cite
Proukakis, C., Houlden, H. and Schapira, A. H. (2013), Somatic alpha-synuclein mutations in Parkinson's disease: Hypothesis and preliminary data. Mov. Disord., 28: 705–712. doi: 10.1002/mds.25502
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online version of this article.
- Issue published online: 25 JUN 2013
- Article first published online: 14 MAY 2013
- Manuscript Accepted: 1 APR 2013
- Manuscript Revised: 13 MAR 2013
- Manuscript Received: 18 NOV 2012
- somatic mutation;
- etiology of Parkinson's disease
Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain-derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. © 2013 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.