Priyanka, P.; Gamliel, A.; Taylor, H.; Ohgi, K. A.; Rosenfeld, M. G.

Chronic oxidative stress is a major contributor to neuronal aging. Due to the lack of homologous recombination (HR) DNA damage repair, high oxygen consumption in neurons causes DNA damage accumulation with age, resulting in a decline in neuronal function, senescence-like phenotypes and onset of neurodegenerative diseases. Here, we identify increased PTBP1 as a stress-inducible negative regulator of neuronal gene expression and senescence-protectant genes. Oxidative stress robustly increases PTBP1 expression in ShSY-5Y differentiated neurons and primary mouse cortical neurons, coinciding with the loss of neuronal genes, including neuronal PTBP2, and activation of stress-responsive genes. Knockdown of PTBP1 in fibroblasts reduces the expression of key senescence genes. Transcriptomic analyses revealed that PTBP1 overexpression results in coordinated shift in gene expression characterized by repression of neuronal commitment genes and activation of stress and senescence genes. Mechanistically, PTBP1 induction is regulated by stress induced CTCF binding at the PTBP1 promoter. Together, our findings suggest that alteration in levels of PTBP1 acts as a molecular switch between neuronal function and survival, providing insight into transcriptional adaptations associated with aging.