{"title":"HDAC6 as a Modulator of DNA Repair in Alzheimer's Disease: From Mechanisms to Therapeutic Perspectives.","authors":"Aneesh Mazumder, Prasenjit Mondal, Can Zhang","doi":"10.1021/acschemneuro.5c00723","DOIUrl":null,"url":null,"abstract":"<p><p>Double-strand breaks (DSBs) are the most cytotoxic DNA damages that arise from endogenous processes (oxidative metabolism as well as external stressors); unrepaired DSBs are consistently found in the hippocampus and cortex of Alzheimer's disease (AD) brains and are thought to contribute to neuronal dysfunction and degeneration. A molecular axis involving histone deacetylase 6 (HDAC6) and an E3 ubiquitin ligase ring finger protein 168 (RNF168) is required for ubiquitination of phosphorylated histone variant H2A.X and the subsequent downstream repair pathway. Herein, we propose that disruption of the HDAC6-RNF168-H2A.X axis is a core mechanism underlying defective DSB repairs in AD and discuss the potential of selectively targeting HDAC6 to restore genomic stability in vulnerable neurons.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acschemneuro.5c00723","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Double-strand breaks (DSBs) are the most cytotoxic DNA damages that arise from endogenous processes (oxidative metabolism as well as external stressors); unrepaired DSBs are consistently found in the hippocampus and cortex of Alzheimer's disease (AD) brains and are thought to contribute to neuronal dysfunction and degeneration. A molecular axis involving histone deacetylase 6 (HDAC6) and an E3 ubiquitin ligase ring finger protein 168 (RNF168) is required for ubiquitination of phosphorylated histone variant H2A.X and the subsequent downstream repair pathway. Herein, we propose that disruption of the HDAC6-RNF168-H2A.X axis is a core mechanism underlying defective DSB repairs in AD and discuss the potential of selectively targeting HDAC6 to restore genomic stability in vulnerable neurons.
期刊介绍：
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research
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