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. H...

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Main Authors: Cheng‐Chun Wu, Lee‐Way Jin, I‐Fang Wang, Wei‐Yen Wei, Pei‐Chuan Ho, Yu‐Chih Liu, Kuen‐Jer Tsai
Format: Article
Language:English
Published: Springer Nature 2020-05-01
Series:EMBO Molecular Medicine
Subjects:
Online Access:https://doi.org/10.15252/emmm.201910622
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author Cheng‐Chun Wu
Lee‐Way Jin
I‐Fang Wang
Wei‐Yen Wei
Pei‐Chuan Ho
Yu‐Chih Liu
Kuen‐Jer Tsai
author_facet Cheng‐Chun Wu
Lee‐Way Jin
I‐Fang Wang
Wei‐Yen Wei
Pei‐Chuan Ho
Yu‐Chih Liu
Kuen‐Jer Tsai
author_sort Cheng‐Chun Wu
collection DOAJ
description 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.
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spelling doaj.art-71d425f1af02490da50e37670dec210f2024-10-28T08:54:17ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-05-0112611710.15252/emmm.201910622HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathiesCheng‐Chun Wu0Lee‐Way Jin1I‐Fang Wang2Wei‐Yen Wei3Pei‐Chuan Ho4Yu‐Chih Liu5Kuen‐Jer Tsai6Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityDepartment of Pathology and Laboratory Medicine, UC Davis Medical CenterInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityAbstract 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.https://doi.org/10.15252/emmm.201910622DNA damageFTLDHDAC1TDP‐43
spellingShingle Cheng‐Chun Wu
Lee‐Way Jin
I‐Fang Wang
Wei‐Yen Wei
Pei‐Chuan Ho
Yu‐Chih Liu
Kuen‐Jer Tsai
HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies
EMBO Molecular Medicine
DNA damage
FTLD
HDAC1
TDP‐43
title HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies
title_full HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies
title_fullStr HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies
title_full_unstemmed HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies
title_short HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies
title_sort hdac1 dysregulation induces aberrant cell cycle and dna damage in progress of tdp 43 proteinopathies
topic DNA damage
FTLD
HDAC1
TDP‐43
url https://doi.org/10.15252/emmm.201910622
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