Exifone is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration

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 patientderived 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.

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

“…Ion transport (45) Regulation of transport (52) Response to external stimulus (49) Secretion (27) Regulation of proteolysis (29) Aging (19) -Log 10 (q value) astrocytes, indicating that HDAC1 maintains genomic integrity in glia as well as neurons (Fig. 2g, h).…”

“…Our previous screening efforts to identify small molecule Ion transport (25) Anion transport (14) Transmembrane transport (19) Reproduction (20) Ion transmembrane transport (16) Overlapping activators of HDAC1 yielded exifone as an HDAC activator and a strong candidate for such a therapeutic strategy ( Supplementary Fig. 9a) 52 . Exifone has also been shown to have pro-cognitive effects in animal models and in patients with Alzheimer's-type dementia and Parkinson's disease [53][54][55][56] .…”

Histone Deacetylases as Epigenetic Targets for Treating Parkinson’s Disease

“…Furthermore, the activation of HDAC1 promoted neuroprotective activity in human neuronal models of neurodegeneration [39]. For Class III HDAC (Sirtuin), SIRT1 and SIRT5 are also known to be neuroprotective while SIRT2, SIRT3 and SIRT6 are known to be neurotoxic [40][41][42].…”

“…There are 18 histone deacetylases in human that may play different role in PD. From the current knowledge, Class I HDACs seem to be neuroprotective while Class II appear to be neurotoxic [38][39][40][41][42]. Especially, the activation of HDAC1, one of Class I HDACs, was beneficial for treating Class III HDACs, was found to be significant overexpression in PD and its regulatory substrates also involved in neurotoxicity and neurodegeneration.…”

Identification and Mechanistic Characterization of a Peptide Inhibitor of Glycogen Synthase Kinase (GSK3β) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein

“…The MST assays were performed as described previously 27 . Similarly, the BLI assays were conducted as described 28 , with the use of biotinylated 6X-His-GSK3b as the recombinant protein.…”