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

Vishnu Dileep; Carles A Boix; Hansruedi Mathys; Asaf Marco; Gwyneth M Welch; Hiruy S Meharena; Anjanet Loon; Ritika Jeloka; Zhuyu Peng; David A Bennett; Manolis Kellis; Li-Huei Tsai

doi:10.1016/j.cell.2023.08.038

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

Cell. 2023 Sep 28;186(20):4404-4421.e20. doi: 10.1016/j.cell.2023.08.038.

Authors

Affiliations

¹ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: vdileep@mit.edu.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Rush Alzheimer's Disease Center, Chicago, IL, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: manoli@mit.edu.
⁶ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: lhtsai@mit.edu.

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: 3D genome organization; Alzheimer’s disease; DNA double-strand breaks; epigenome; genome rearrangements; genomic mosaicism; neurodegeneration; senescence; structural variations; transcriptome.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease / genetics
Animals
DNA
DNA Breaks, Double-Stranded*
DNA Repair / genetics
Genomic Instability
Humans
Mice
Neurodegenerative Diseases* / genetics
Neurons / physiology
Sequence Analysis, RNA
Single-Cell Analysis

Substances

DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding