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 one histone deacetylase HDAC1 has been identified as a critical protein for protecting neurons from deleterious effects mainly caused by double strand DNA breaks in Alzheimers 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 one HDACs. Here, we demonstrate that exifone, a drug previously shown to be effective in treating cognitive decline associated with AD and Parkinsons 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 one HDACs and CDK5. Treatment of human induced pluripotent stem cell derived neuronal cells resulted in a decrease of histone acetylation, consistent with an intracellular mechanism of deacetylase activation. Moreover, using tauopathy patient-derived induced pluripotent stem cell 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.

中文翻译：

---

Exifone是有效的HDAC1激活剂，在人类神经变性神经元模型中具有神经保护活性

DNA损伤反应和修复不足引起的基因组不稳定与年龄相关的认知能力下降和神经退行性疾病有关。防止这种基因组完整性的丧失最终导致神经元死亡，可以提供一种广泛有效的策略来预防多种潜在的遗传毒性应激源。最近，锌依赖性的一类组蛋白脱乙酰基酶HDAC1被确定为保护神经元免受主要由阿尔茨海默氏病（AD），肌萎缩性侧索硬化（ALS）和额颞痴呆（FTD）引起的双链DNA断裂所致有害作用的关键蛋白。 ）。将这些观察结果转化为AD的新型神经保护疗法，ALS或FTD将受益于鉴定出能够选择性提高HDAC1的脱乙酰酶活性的小分子，而这些小分子相对于其他结构相似的一级HDAC。在这里，我们证明了exifone是一种先前显示出可有效治疗与AD和帕金森病相关的认知衰退的药物，其分子机制仍知之甚少，可以有效激活HDAC1的脱乙酰基酶活性并提供针对基因毒性压力的保护作用。我们显示，exifone充当HDAC1的混合的，非必要的激活剂，能够与游离和底物结合的酶结合，从而导致HDAC1催化脱乙酰基的相对最大速率增加。使用生物层干涉测量法进行选择性分析和动力学参数估计表明，与其他第一类HDAC和CDK5相比，HDAC1是优先目标。人类诱导的多能干细胞衍生神经元细胞的治疗导致组蛋白乙酰化的减少，这与脱乙酰酶激活的细胞内机制一致。此外，使用tauopathy的患者源性诱导多能干细胞神经元模型通过线粒体抑制作用受到氧化应激，exifone治疗具有神经保护作用。综上所述，这些发现揭示了exifone作为HDAC1介导的脱乙酰基作用的有效激活剂，从而为旨在保护神经变性和衰老的基因组完整性的新型治疗方法提供了线索。人类诱导的多能干细胞衍生神经元细胞的治疗导致组蛋白乙酰化的减少，这与脱乙酰酶激活的细胞内机制一致。此外，使用tauopathy的患者源性诱导多能干细胞神经元模型通过线粒体抑制作用受到氧化应激，exifone治疗具有神经保护作用。综上所述，这些发现揭示了exifone作为HDAC1介导的脱乙酰基作用的有效激活剂，从而为旨在保护神经变性和衰老的基因组完整性的新型治疗方法提供了线索。人类诱导的多能干细胞衍生神经元细胞的治疗导致组蛋白乙酰化的减少，这与脱乙酰酶激活的细胞内机制一致。此外，使用tauopathy的患者源性诱导多能干细胞神经元模型通过线粒体抑制作用受到氧化应激，exifone治疗具有神经保护作用。综上，这些发现揭示了exifone作为HDAC1介导的脱乙酰基作用的有效激活剂，从而为旨在保护神经变性和衰老背景下的基因组完整性的新型治疗方法提供了线索。使用tauopathy源自患者的诱导多能干细胞神经元模型通过线粒体抑制作用受到氧化应激，exifone治疗具有神经保护作用。综上所述，这些发现揭示了exifone作为HDAC1介导的脱乙酰基作用的有效激活剂，从而为旨在保护神经变性和衰老的基因组完整性的新型治疗方法提供了线索。使用tauopathy源自患者的诱导多能干细胞神经元模型通过线粒体抑制作用受到氧化应激，exifone治疗具有神经保护作用。综上所述，这些发现揭示了exifone作为HDAC1介导的脱乙酰基作用的有效激活剂，从而为旨在保护神经变性和衰老的基因组完整性的新型治疗方法提供了线索。