Loss of HDAC1 compromises genomic integrity, aggravates brain aging and Alzheimer’s disease pathology

Identification: Pao, Ping-Chieh


Description

Loss of HDAC1 compromises genomic integrity, aggravates brain aging and Alzheimer's disease pathology
 
Ping-Chieh Pao1,2, Lauren Ashley Watson1,2, Fan Gao1,2, Chinnakkaruppan Adaikkan1,2, Ling Pan1,2, Sara Elmsaouri1,2, Debasis Patnaik3, Stephen J. Haggarty3, Li-Huei Tsai1,2,*
1Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; USA; 2Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 3Chemical Neurobiology Laboratory, Departments of Psychiatry & Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
*Corresponding Author
 
Genomic instability is considered one of causative factors contributing to brain aging. During aging, DNA damage accumulates, but the capacity for DNA repair is compromised, which leads to functional decline and increased vulnerability of the brain to age-related neurodegenerative disorders. Our previous studies have revealed that upon DNA double-strand breaks (DSBs), class I histone deacetylase HDAC1 is recruited to break sites and is necessary for DSBs repair through the non-homologous end-joining pathway in the collaboration with SIRT1 and FUS. In this study, we attempt to elucidate the roles of HDAC1 in brain aging and Alzheimer's disease in vivo. We show that Hdac1 brain-specific knockout mice manifest various aging phenotypes, including increased DNA damage, profound reactive gliosis, impaired spatial memory and reduced induction of long-term potentiation in the hippocampus. Deficiency of HDAC1 in a mouse model of Alzheimer's disease further aggravates genomic instability and increases amyloid plaque deposition. Pharmacological activation of HDAC1 is able to ameliorate DNA damage that occurs during normal aging of wild-type mice. Our findings suggest that promoting HDAC1 activity offers a viable therapeutic avenue in maintaining genomic integrity during brain aging. 
 

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