Language
English
Publication Date
9-28-2023
Journal
Cell
DOI
10.1016/j.cell.2023.08.038
PMID
37774679
PMCID
PMC10697236
PubMedCentral® Posted Date
12-5-2023
PubMedCentral® Full Text Version
Author MSS
Abstract
Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human postmortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.
Keywords
Animals, Humans, Mice, Alzheimer Disease, DNA, DNA Breaks, Double-Stranded, DNA Repair, Neurodegenerative Diseases, Neurons, Single-Cell Analysis, Sequence Analysis, RNA, Genomic Instability, Neurodegeneration, DNA double-strand breaks, Alzheimer’s Disease, Structural Variations, 3D genome organization, Genomic Mosaicism, Somatic Mosaicism, Epigenome, Transcriptome, Senescence
Published Open-Access
yes
Recommended Citation
Marco, Asaf; Welch, Gwyneth M; Meharena, Hiruy S; et al., "Neuronal Dna Double-Strand Breaks Lead to Genome Structural Variations and 3D Genome Disruption in Neurodegeneration" (2023). Faculty, Staff and Students Publications. 8554.
https://digitalcommons.library.tmc.edu/baylor_docs/8554