The role of somatic mutation in neurodegenerative disease

Boston Children'S Hospital, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Ataxia-Telangiectasia (AT) is an incurable childhood disorder characterized by accelerated aging and progressive cerebellum degeneration causing several disabilities. Despite the discovery of causative mutations in the gene ATM (AT-mutated), its unknown pathogenic mechanism makes developing a treatment extremely difficult. It is known that ATM senses DNA double strand breaks (DSBs) and triggers downstream repair pathways including cell-cycle arrest and apoptosis. The lack of proper DSB repair due to the inherited ATM mutation in AT is thought to lead to the accumulation of unrepaired DSBs and increase genomic instability such as genomic rearrangement and aneuploidy. However, it is unclear how abnormal DSB repair relates to genomic instability and how the genomic instability impacts pathogenicity. Recent studies have reported frequent retrotransposition of transposable elements (TEs) in engineered ATM-deficient cells, increased DNA copies of TEs in AT patient brains, and abnormal expression of satellite repeats in DSB repair defective cells. Along with our published and unpublished data, these suggest a hypothesis that repeat aberrations may be a frequent form of genomic instability and pathogenic in AT. Our published single-neuron analysis showed that somatic retrotransposition occurred in neuronal progenitors and it created low-level somatic mosaicism in normal human brain. This suggests hypotheses that 1) neurons in AT patients may have a mixed population of somatic mutations occurring at different time points during development, and 2) late mutations present in a limited number of neurons may be critical determinants of cell death. Because those rare mutations cannot be detected with typical pooled-cell analysis, we propose to analyze genomes of individual neurons. However, the single-cell genomic approaches need to address significant technical challenges introduced by the whole genome amplification process necessary in current single-cell sequencing techniques. Thus, with a development of novel computational methods, we will characterize somatic mutations leading to multiple forms of genomic instability, including repeat aberration, in AT and assess their functional impact to neurodegeneration.