HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP-43 proteinopathies

Cheng Chun Wu, Lee Way Jin, I. Fang Wang, Wei Yen Wei, Pei Chuan Ho, Yu Chih Liu, Kuen Jer Tsai

研究成果: 雜誌貢獻文章同行評審

12 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
文章編號e10622
期刊EMBO Molecular Medicine
12
發行號6
DOIs
出版狀態已發佈 - 6月 8 2020
對外發佈

ASJC Scopus subject areas

  • 分子醫學

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