Author Interviews, Cognitive Issues / 12.06.2015
Defects in DNA Repair Could Underlie Cognitive Decline
MedicalResearch.com Interview with:
Dr. Li-Huei Tsai Ph.D.
Professor and Director - Picower Institute
For Learning and Memory
Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology
Medical Research: What is the background for this study? What are the main findings?
Dr. Tsai: For a while now, we have been interested in observations made by many labs, including our own, that the accumulation of DNA lesions is a hallmark of the aging brain, and that mutations in DNA repair factors manifest in congenital and neurodegenerative disorders. However, the precise contribution of unrepaired DNA lesions to the development of neurological disorders remains poorly understood. A major confounding factor is that the sources that generate DNA lesions in the brain are not well characterized, and it is not known whether damage accumulates non-specifically throughout the genome, or whether there are certain regions that are more prone to accumulate DNA damage.
In this regard, our study reports three major findings:
(1) Physiological neuronal activity itself results in the formation of DNA breaks;
(2) Neuronal activity-induced DNA breaks form at highly specific locations, including within the promoters of a subset of immediate early genes, including Fos, Npas4, and Egr1. These genes are also rapidly expressed in response to neuronal stimulation, and play crucial roles in experience-driven changes to synapses, and learning and memory;
(3) Neuronal activity-induced breaks are generated by a topoisomerase, Topo IIβ, and Topo IIβ-generated DNA breaks facilitate the rapid expression of these immediate early genes following neuronal stimulation. (more…)