Abstract
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 Movement Disorder Society
Highlights
Alpha-synuclein (SNCA), encoded by the SNCA (PARK1) gene, is central to the pathogenesis of Parkinson’s disease (PD).[1,2] It is the major component of Lewy bodies
Because of the a priori very low likelihood of an apparently sporadic late-onset PD case harboring a novel heterozygous missense mutation, we considered the possibility that the patient in whom we recently detected the novel c.150T>G (p.H50Q) mutation in the substantia nigra (SN) and cerebellum[6] might have been a mosaic for a somatic mutation
The orderly progression described by Braak[40] may explain this, we propose that the widespread early distribution of PD pathology could be partly explained by somatic mutations arising by the third week of embryogenesis; this would lead to neurons carrying the mutations found in all 3 primary brain vesicles and the neural crest (Fig. 4)
Summary
Alpha-synuclein (SNCA), encoded by the SNCA (PARK1) gene, is central to the pathogenesis of Parkinson’s disease (PD).[1,2] It is the major component of Lewy bodies. Misfolding into oligomers and fibrils is believed to underlie its toxicity, the precise nature of the toxic species remains unclear. Three SNCA missense mutations have been reported in pedigrees with autosomal dominant inheritance.[3,4,5] We recently identified the c.150T>G/p.H50Q mutation in Additional Supporting Information may be found in the online version of this article
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