Mechanisms of Activity-Dependent Transcription and DNA Repair in Neuronal Longevity

The overarching goal of this proposal is to define new mechanisms that promote neuronal DNA repair and transcriptional fidelity across lifespan. The number of diagnoses for age-dependent neurodegenerative disease and dementia is projected to more than double by 2050, underscoring our immediate need to understand the cellular and molecular basis of brain aging. A critical aspect of age-dependent cognitive decline is the decreased ability of neurons to adapt to experience-driven changes in neuronal activity. Neuronal activity promotes plasticity, in part, via the de novo induction of cell-type-specific transcriptional programs that mediate learning and memory. However, the induction of such activity-dependent programs drives DNA damage at gene regulatory elements. Neuronal activity is thus a risky endeavor: long-lived neurons must adapt to new cues to facilitate life-long learning and yet maintain a pristine genome. Although accumulating DNA damage is a hallmark of aging and neurodegeneration, our knowledge of the mechanisms that limit damage in post-mitotic neurons is surprisingly limited. How neurons balance transcription and repair, especially in the context of aging neural circuits, is a fundamental unanswered question with major implications for cognitive aging and neurodegenerative disease. Here, we will leverage our lab’s recent discovery that neurons couple activity-dependent transcription to DNA repair through the neuronal chromatin modifier, NPAS4:NuA4. Deletion of NPAS4:NuA4 components in mouse models leads to dysregulated transcriptional responses to activity and increased DNA double-strand breaks across the genome, culminating in drastically reduced organismal longevity. Npas4 expression is reduced in aged neurons, suggesting dysregulation of transcriptional control and genome protection by NPAS4:NuA4 contributes to age-associated neuronal dysfunction. However, the mechanisms by which this protective complex stimulates both transcription and repair remain unclear. We hypothesize that NPAS4:NuA4 promotes genome stability via homology-directed repair factors and enhances transcriptional fidelity during aging via chromatin control of RNA Polymerase II (RNAPII) speed. In Aim 1, we will examine a role for the homology-directed repair factor RAD52 downstream of NPAS4:NuA4 in active neurons and test the consequences of perturbing this pathway on cellular aging phenotypes. In Aim 2, we will assess age-dependent changes to the regulation of activity-dependent transcriptional programs, especially those mediated by NPAS4:NuA4. These mechanistic studies will enhance foundational knowledge of genome control in post- mitotic cells and position us to design strategies that slow or prevent molecular damage in aged and diseased human neurons. Project Number: 1R01AG098482-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Elizabeth Pollina | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $593,146 | Activity Code: R01 | Study Section: Cellular Mechanisms in Aging and Development Study Section[CMAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11275589