Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
EMBO Mol Med. 2020 Jun 8;12(6):e10622. doi: 10.15252/emmm.201910622. Epub 2020 May 25.
TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.
TAR DNA 结合蛋白 43（TDP-43）与泛素阳性包涵体（FTLD-TDP）和肌萎缩侧索硬化症有关。组蛋白去乙酰化酶 1（HDAC1）参与多种神经退行性疾病的 DNA 修复和神经保护。然而，TDP-43 蛋白病引起的 FTLD-TDP 的病理机制尚不清楚，HDAC1 的作用也知之甚少。在这里，我们发现异常的细胞周期活动和 DNA 损伤是 FTLD-TDP 转基因（Tg）小鼠的重要致病因素，并且我们进一步在 FTLD-TDP 患者的额皮质中鉴定了这些病理特征。TDP-43 蛋白病通过诱导 HDAC1 的细胞质错位和降低其活性来促进发病。在 FTLD-TDP Tg 小鼠中恢复 HDAC1 活性的药理学方法改善了它们的认知和运动障碍，使它们的异常细胞周期活动正常化，并减轻了它们的 DNA 损伤和神经元丢失。因此，HDAC1 失调参与了 TDP-43 蛋白病的发病机制，HDAC1 是治疗 FTLD-TDP 的潜在靶点。
