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Naik, S. M.

Publications and source records attributed to Naik, S. M..

2 recordsLinked to original sources
bioRxiv2025

Neurons accumulate disease-specific somatic genomic changes across taupathologic states in Alzheimer's disease

Tau deposition within neurons marks Alzheimers disease (AD) neuropathology, suggesting that tau may contribute to cellular dysfunction and death. In AD, somatic mutations accumulate in neurons, with features that suggest deleterious effects on cellular function. To examine the relationship between tau and somatic mutation, we isolated neurons according to tau pathology and performed single-cell whole-genome sequencing on tau+, tau-, and tau-agnostic neurons from 13 individuals with AD, as well as neurons from 15 control individuals. We found that AD neurons, regardless of tau status, exhibited an increased burden of somatic single-nucleotide variants (sSNVs) and insertions and deletions (sIndels). Mutational signature analyses revealed disease-specific patterns, including sIndels characterized by two-basepair (2bp) deletions, indicating shared mutagenic mechanisms in AD neurons across tau pathologic cell states. Somatic mutations are associated with tissue-wide tau pathology, suggesting that tangles do not confer cell-autonomous genotoxicity to neurons and that non-tangle components drive somatic mutation in AD.

genomics↗
bioRxiv2025

Diverse somatic genomic alterations in single neurons in chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is linked to exposure to repetitive head impacts (RHI), yet little is known about its pathogenesis. Applying two single-cell whole-genome sequencing methods to hundreds of neurons from prefrontal cortex of 15 individuals with CTE, and 4 with RHI without CTE, revealed increased somatic single-nucleotide variants in CTE, resembling a pattern previously reported in Alzheimers disease (AD). Furthermore, we discovered remarkably high burdens of somatic small insertions and deletions in a subset of CTE individuals, resembling a known pattern, ID4, also found in AD. Our results suggest that neurons in CTE experience stereotyped mutational processes shared with AD; the absence of similar changes in RHI neurons without CTE suggests that CTE involves mechanisms beyond RHI alone.

genomics↗