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HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease

Pao, Ping-Chieh and Patnaik, Debasis and Watson, L. Ashley and Gao, Fan and Pan, Ling and Wang, Jun and Adaikkan, Chinnakkaruppan and Penney, Jay and Cam, Hugh P. and Huang, Wen-Chin and Pantano, Lorena and Lee, Audrey and Nott, Alexi and Phan, Trongha X. and Gjoneska, Elizabeta and Elmsaouri, Sara and Haggarty, Stephen J. and Tsai, Li-Huei (2020) HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nature Communications, 11 . Art. No. 2484. ISSN 2041-1723. PMCID PMC7235043. doi:10.1038/s41467-020-16361-y.

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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.

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URLURL TypeDescription CentralArticle
Pao, Ping-Chieh0000-0001-6788-7185
Patnaik, Debasis0000-0002-9829-3352
Pantano, Lorena0000-0002-3859-3249
Nott, Alexi0000-0002-2029-7193
Haggarty, Stephen J.0000-0002-7872-168X
Tsai, Li-Huei0000-0003-1262-0592
Additional Information:© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 28 March 2019; Accepted 28 April 2020; Published 18 May 2020. We thank E.N. Olson (University of Texas Southwestern Medical Center) for providing Hdac1^(f/f) mice. We also thank E. McNamara and M. Taylor for mouse colony maintenance; BioMicro Center at MIT for library preparation of RNA-seq; R. Madabhushi, C.-Y. Wang and members of Tsai lab for discussion and valuable comments on manuscript. S.J.H. received funding from an Alzheimer’s Association New Investigator Research Grant and Stuart & Suzanne Steele MGH Research Scholars Program. This work was supported by NIA Grant (AG046174), NINDS Grant (NS102730), and Glenn Foundation Award for research in biological mechanisms of aging to L.-H.T. Data availability: Source data underlying Figs. 1b,d–i, 2b, d, f, h, 3, 4b, f, 5b–d, f–i, and 6a–c, e–g and Supplementary Figs. 1a, d, f–i, 2a, b, d, e, 3–6, 7c, 8b, 9b–i, 10c–f, 11–13, and 14b are available as a Source Data file. All other relevant data supporting this study are available from the corresponding author upon reasonable request. Cell-type enrichment of DEGs was using published cell-type-specific mouse dataset (, Brain RNA-seq dataset). Sequencing datasets are available to the public in the GEO Data Bank under accession numbers GSE115437 and GSE147407. Author Contributions: P.-C.P. and L.-H.T. designed the study, and L.-H.T. directed and coordinated the study. P.-C.P. initiated, planned, and performed most of the experiments. L.A.W. and P.-C.P. optimized and conducted the comet assay. F.G. conducted bioinformatics analysis. D.P. and S.J.H. identified exifone as an HDAC1 activator, and provided data regarding exifone concentration in mouse brain. L.Pan, P.-C.P. and A.L. performed exifone treatment in primary neuronal culture and L.Pan conducted RNA-seq analysis using 3-month-old animals. J.W. conducted the electrophysiological experiments. C.A. conducted viral injection and W.-C.H. performed cannula implantation. L.Pantano analyzed the enrichment of DEGs corresponding to specific brain cell types. A.N., T.X.P. and E.G. conducted the HDAC1 ChIP-seq experiment. S.E. and A.L. performed qPCR analysis and A.L. contributed to quantification of experiments. P.-C.P., J.P., H.P.C. and L.-H.T. wrote the manuscript with critical input from all of the authors. Competing interests: S.J.H. is a member of the scientific advisory board of Psy Therapeutics and Frequency Therapeutics neither of whom were involved in the present study. L.-H.T. and S.J.H. are also co-founders and members of Scientific Advisory Board of Souvien Therapeutics. L.-H.T., S.J.H., P.-C.P., D.P. and L.Pan have licensed intellectual property related to HDAC1 activators. The remaining authors declare no competing interests. Peer review information: Nature Communications thanks J. Pablo Radicella and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Funding AgencyGrant Number
Alzheimer’s AssociationUNSPECIFIED
Stuart and Suzanne Steele MGH Research Scholars ProgramUNSPECIFIED
Glenn Family FoundationUNSPECIFIED
Subject Keywords:Alzheimer's disease; Cognitive ageing; DNA damage and repair; Learning and memory; Neurodegeneration
PubMed Central ID:PMC7235043
Record Number:CaltechAUTHORS:20200526-084540459
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Official Citation:Pao, P., Patnaik, D., Watson, L.A. et al. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nat Commun 11, 2484 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103440
Deposited By: Tony Diaz
Deposited On:26 May 2020 16:32
Last Modified:16 Nov 2021 18:21

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