Somatic mutations in neurodegeneration: An update

• Main Author: Christos Proukakis
• Format: Article
• Language: English
• Published: Elsevier 2020-10-01
• Series: Neurobiology of Disease
• Subjects: Somatic mutation; Mosaicism; Neurodegeneration; Single cell sequencing; Synucleinopathy; Huntington's disease
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996120302965

Mosaicism, the presence of genomic differences between cells due to post-zygotic somatic mutations, is widespread in the human body, including within the brain. A role for this in neurodegenerative diseases has long been hypothesised, and technical developments are now allowing the question to be addressed in detail. The rapidly accumulating evidence is discussed in this review, with a focus on recent developments. Somatic mutations of numerous types may occur, including single nucleotide variants (SNVs), copy number variants (CNVs), and retrotransposon insertions. They could act as initiators or risk factors, especially if they arise in development, although they could also result from the disease process, potentially contributing to progression. In common sporadic neurodegenerative disorders, relevant mutations have been reported in synucleinopathies, comprising somatic gains of SNCA in Parkinson’s disease and multiple system atrophy, and in Alzheimer’s disease, where a novel recombination mechanism leading to somatic variants of APP, as well as an excess of somatic SNVs affecting tau phosphorylation, have been reported. In Mendelian repeat expansion disorders, mosaicism due to somatic instability, first detected 25 years ago, has come to the forefront. Brain somatic SNVs occur in DNA repair disorders, and there is evidence for a role of several ALS genes in DNA repair. While numerous challenges, and need for further validation, remain, this new, or perhaps rediscovered, area of research has the potential to transform our understanding of neurodegeneration.