Neurons accumulate disease-specific somatic genomic changes across taupathologic states in Alzheimer's disease
Jin, B.; Brown, K. S.- M.; Smirnov, D. S.; Naik, S. M.; Kirkham, S. L.; Hennessey, E. L.; Dong, G.; Mao, S.; Wijethunga, S. P.; Stewart, T. C.; Selkoe, D. J.; Frosh, M. P.; Oakley, D. H.; Hyman, B. T.; Huang, A. Y.; Miller, M.
Show abstract
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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Polygenic burden of short tandem repeat expansions promote risk for Alzheimer’s disease 96%
- Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease 96%
- Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states 96%
Similar papers in this journal
- Neuronal pentraxin Nptx2 regulates complement activity in the brain 92%
- Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction 91%
- The SARS-CoV-2 mRNA-1273 vaccine elicits more RBD-focused neutralization, but with broader antibody binding within the RBD 91%
Similar papers in this journal
- ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration 97%
- Amyloid Beta Glycation Induces Neuronal Mitochondrial Dysfunction and Alzheimers Pathogenesis via VDAC1-Dependent mtDNA Efflux 95%
- S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.