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...
Main Authors: | , , , , , , |
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Language: | English |
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Springer Nature
2020-05-01
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Series: | EMBO Molecular Medicine |
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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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issn | 1757-4676 1757-4684 |
language | English |
last_indexed | 2025-02-18T14:18:52Z |
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publisher | Springer Nature |
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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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