@article{5b5e07d928d74067ad34cea88703c780,
title = "HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP-43 proteinopathies",
abstract = "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.",
keywords = "DNA damage, FTLD, HDAC1, TDP-43",
author = "Wu, {Cheng Chun} and Jin, {Lee Way} and Wang, {I. Fang} and Wei, {Wei Yen} and Ho, {Pei Chuan} and Liu, {Yu Chih} and Tsai, {Kuen Jer}",
note = "Funding Information: The authors are grateful to University of California Davis Alzheimer's Disease Center, funded by National Institute on Aging (NIA, grant #P30AG10129) for collecting and providing the human samples. This study was performed, in part, with support from Taiwan Ministry of Science and Technology (NSC‐102‐2320‐B‐006‐040‐MY3, MOST‐103‐2321‐B‐006‐028, MOST‐104‐2321‐B‐006‐010, MOST‐105‐2321‐B‐006‐ 002, MOST‐105‐2628‐B‐006‐016‐MY3, and MOST‐106‐2628‐B‐006‐001‐MY4). Funding Information: The authors are grateful to University of California Davis Alzheimer's Disease Center, funded by National Institute on Aging (NIA, grant #P30AG10129) for collecting and providing the human samples. This study was performed, in part, with support from Taiwan Ministry of Science and Technology (NSC-102-2320-B-006-040-MY3, MOST-103-2321-B-006-028, MOST-104-2321-B-006-010, MOST-105-2321-B-006- 002, MOST-105-2628-B-006-016-MY3, and MOST-106-2628-B-006-001-MY4). Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = jun,
day = "8",
doi = "10.15252/emmm.201910622",
language = "English",
volume = "12",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "6",
}