Abstract:
Genomic instability caused by a deficiency in the DNA damage response and repair has been linked to age-related cognitive decline and neurodegenerative disease. Preventing this loss of genomic integrity 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 protein for protecting neurons from deleterious effects mainly caused by double-strand DNA breaks in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Translating these observations to a novel neuroprotective therapy for AD, ALS or FTD will benefit from the identification of small molecules capable of selectively increasing the deacetylase activity of HDAC1 over other structurally similar class I HDACs. Here, we demonstrate that exifone, a drug previously shown to be effective in treating cognitive decline 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. Selectivity profiling and estimation of kinetic parameters using biolayer interferometry suggest HDAC1 is a preferential target compared to other class I HDACs and CDK5. Treatment of human induced pluripotent stem cell (iPSC)-derived neuronal cells resulted in a decrease of histone acetylation, consistent with an intracellular mechanism of deacetylase activation. Moreover, using tauopathy patient-derived iPSC neuronal models subject to oxidative stress through mitochondrial inhibition exifone treatment was neuroprotective. 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.
