%0 Journal Article %A Debasis Patnaik %A Ping-Chieh Pao %A Wen-Ning Zhao %A M. Catarina Silva %A Norma K. Hylton %A Peter S. Chindavong %A Ling Pan %A Li-Huei Tsai %A Stephen J. Haggarty %T Exifone is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration %D 2020 %R 10.1101/2020.03.02.973636 %J bioRxiv %P 2020.03.02.973636 %X Genomic instability caused by a deficiency in the DNA damage response and repair has been linked to age-related cognitive decline and neurodegenerative diseases. Preventing genomic instability that ultimately leads to neuronal death may provide a broadly effective strategy to protect against multiple potential genotoxic stressors. Recently, the zinc-dependent, class I histone deacetylase HDAC1 has been identified as a critical factor for protecting neurons from deleterious effects of DNA damage in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Translating these observations to a novel neuroprotective therapy for AD, ALS, and FTD may be advanced by the identification of small molecules capable of increasing the deacetylase activity of HDAC1 selectively over other structurally similar HDACs. Here, we demonstrate that exifone, a drug previously shown to be effective in treating cognitive deficits associated with AD and Parkinson’s disease, the molecular mechanism of which has remained poorly understood, potently activates the deacetylase activity of HDAC1 and provides protection against genotoxic stress. We show that exifone acts as a mixed, non-essential activator of HDAC1 that is capable of binding to both free and substrate-bound enzyme resulting in an increased relative maximal rate of HDAC1-catalyzed deacetylation. Exifone can directly bind to HDAC1 based upon biolayer interferometry assays with kinetic and selectivity profiling suggesting HDAC1 is preferentially targeted compared to other class I HDACs and the kinase CDK5 that have also been implicated in neurodegeneration. Consistent with a mechanism of deacetylase activation intracellularly, treatment of human induced pluripotent stem cell (iPSC)-derived neuronal cells resulted in globally decreased histone acetylation. Moreover, exifone treatment was neuroprotective in a tauopathy patient iPSC-derived neuronal model subject to oxidative stress. Taken together, these findings reveal exifone as a potent activator of HDAC1-mediated deacetylation, thereby offering a lead for novel therapeutic development aiming to protect genomic integrity in the context of neurodegeneration and aging.Competing Interest StatementS.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. S.J.H. has also received speaking or consulting fees from Amgen, AstraZeneca, Biogen, Merck, Regenacy Pharmaceuticals, Sunovion, and Syros Pharmaceuticals, as well as sponsored research or gift funding from AstraZeneca, JW Pharmaceuticals, and Vesigen unrelated to the content of this manuscript. Dr. Haggarty is also a founder and member of the scientific advisory board of Souvien Therapeutics, which aims to address the loss of cognitive ability conditions through drug-induced improvements in genomic integrity and has licensed technology related to HDAC1 activators from Massachusetts General Hospital and Massachusetts Institute of Technology. Dr. Haggarty s interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict of interest policies. D.P., P.-C.P., W.-N.Z., M.C.S, N.K.H., P.S.C., and L.P. reported no biomedical financial interests or potential conflicts of interest. %U https://www.biorxiv.org/content/biorxiv/early/2020/05/23/2020.03.02.973636.full.pdf