HDAC6 as a Modulator of DNA Repair in Alzheimer’s Disease: From Mechanisms to Therapeutic Perspectives

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.