Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits

TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.