HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
Name
s41467-020-16361-y.pdf
Description
Published version
Size
3.02 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Pao, Ping-Chieh
Patnaik, Debasis
Watson, L Ashley
Gao, Fan
Pan, Ling
Wang, Jun
Adaikkan, Chinnakkaruppan
Penney, Jay
Cam, Hugh P
Huang, Wen-Chin
Date Issued
2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 2020, The Author(s). DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer’s disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.
MIT Department
Picower Institute for Learning and Memory
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1038/S41467-020-16361-Y
