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Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration [Mate-Pair]

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 show increased mosaic structural variations and gene fusions in neurons burdened with DSBs in the CK-p25 inducible mouse model of neurodegeneration. Next, we used full-transcript single-nucleus RNA-seq across 47 human post-mortem prefrontal cortex and find that excitatory neurons in AD are enriched for mosaic gene fusions. In addition, gene fusions are particularly enriched in excitatory neurons with senescence and DNA repair gene signatures. Neurons enriched for DSBs also have elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic and neuronal development 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE227444 | GEO | 2023/09/27

REPOSITORIES: GEO

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Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration [Mate-Pair]

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