Activity-Dependent DNA Damage: A New Mechanism of Selective Cell Vulnerability

A striking feature of the nervous system is its continual adaptation to environmental cues throughout life. Environmental stimuli trigger changes in neuronal activity which, in turn, induce transcriptional programs that drive adaptive modifications to neuronal circuits. However, during transcription, DNA can be cut, unwound, the reannealed in a process that has the potential to create mutations. How then do animals balance the necessity of activity for brain plasticity with the intrinsic risk it poses to the genetic code? How is this balance achieved over decades in humans and other long-lived species?

Accumulating DNA damage to neuronal genomes an emerging feature of normal aging and neurodegeneration. Yet, we know remarkably little about how the brain’s mature cell types prevent and repair damage nor how changing patterns of activity across a lifetime impinge on genome stability. Until recently, the field has lacked the tools to probe mechanisms of genome stability in a tissue as complex as the brain. My lab overcame these barriers to discover that neuronal activity is not just a source of damage; it also stimulates unique pathways of DNA repair. We leverage our interdisciplinary expertise in neuroscience, genomics, and DNA repair to define new genome protection mechanisms that can preserve vulnerable cell types in aging and degeneration. In the short term, we aim to identify the brain cell types most vulnerable to damage and the molecular pathways that can be manipulated to protect them. In the long term, this mechanistic knowledge can help us understand how lifestyle factors that drive neuronal activity - sleep loss, stress, diet - influence damage and repair to affect disease risk with age. Ultimately, we want to harness the protective pathways we discover to slow or even correct molecular damage in human brain aging and degenerative disease.

Dr. Pollina is a molecular neuroscientist studying the mechanisms that preserve longevity and promote rejuvenation in the nervous system. She is an Assistant Professor in the Department of Developmental Biology at Washington University in St. Louis. The Pollina Lab uses molecular, genomic, and systems neuroscience approaches to uncover how neuronal function is maintained over time and how these mechanisms break down in aging and disease. Dr. Pollina trained in Molecular Biology as an undergraduate at Princeton University. She went on to earn her PhD in Cancer Biology at Stanford University and completed her postdoctoral training in molecular neurobiology at Harvard Medical School.  In addition the MIND prize, she has been the recipient of several honors, including a NIH K99/R00 transition award, a Rita Allen Scholarship, and a Klingenstein-Simons Fellowship in Neuroscience.

This project seeks to uncover how our long-lived neurons protect their genomes from damage across time and its relevance to devastating degenerative diseases. Neurons face a surprising source of damage to the genome – the physiological process of neuronal activation that is essential for learning, memory, and behavior. We believe neurons have evolved specialized systems to counteract the risk of activity and preserve their genomes. We hypothesize that activity-dependent DNA damage is a potent mechanism by which our life experiences (e.g. poor sleep, stress) are encoded as a molecular memory on the genome to enhance vulnerability to disease with age. Such memories could be erased by efficient genome repair.  With support from the MIND Prize, we will combine tools for precise control of neuronal activity with cutting-edge methods for genome-wide mapping of DNA breaks and mutations in the brain. We will develop unbiased CRISPR screens to identify new factors that suppress mutational accumulation in different brain cell types during aging. In longer term goals, we will study how lifestyle factors, beginning with changes in sleep, influence DNA damage and repair in neurons across the brain and body.