12 Jun 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.

Medical Research: What should clinicians and patients take away from your report?

Dr. Tsai: First, that DNA breaks are an important component of normal physiological activity in neurons.

Second, because activity-induced DNA breaks form at the promoters of genes that mediate experience-driven changes in the brain, any change in a neuron’s ability to repair such lesions is likely to have important physiological and pathological implications. Our observations underscore the importance of mechanisms that ensure that neuronal activity-induced DNA breaks are repaired accurately. Defects that compromise these repair mechanisms could underlie cognitive decline with age and in neurodegenerative disorders.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Tsai: An exciting avenue of future research would be to identify the mechanisms that ensure that neuronal activity-induced DNA breaks are accurately repaired. This information could then be used to address the important question of whether the formation and repair of activity-induced DNA breaks underlie cognitive decline with age or during the development of neurodegenerative disorders. Identification of mechanisms that affect these processes are also likely to provide new targets for therapeutic intervention.

Citation:

Li-Huei Tsai et al. Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell, June 2015 DOI: 10.1016/j.cell.2015.05.032

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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 (2015). Defects in DNA Repair Could Underlie Cognitive Decline 

Last Updated on June 12, 2015 by Marie Benz MD FAAD