Elevated neuronal TAF15 expression leads to FTD-like phenotype

TAF15, a DNA/RNA-binding protein whose dysfunction in alternative splicing impairs NMDA receptor signaling, can form amyloid fibrils that contribute to neurodegeneration in the neurodegenerative diseases like FTD and ALS, indicating a close involvement of TAF15 in both neuronal physiological function and activation of pathological pathways. However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remains unclear. Here, we found a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrated that neuronal TAF15 overexpression triggered oxidative stress, evidenced by reactive oxygen species (ROS) production, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibited heightened anxiety and impaired fear memory, mimicking some key features of FTD behavioral abnormalities. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), indicating that elevated TAF15 level exacerbates neurodegeneration primarily by activating oxidative stress pathways. Together, this work elucidates a novel TAF15-oxidative stress axis in FTD-associated neurodegeneration, providing a conceptual framework for future therapeutic development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/694105v1_ufig1.gif" ALT="Figure 1000"> View larger version (35K): org.highwire.dtl.DTLVardef@cc581eorg.highwire.dtl.DTLVardef@1ad2129org.highwire.dtl.DTLVardef@15c0fb5org.highwire.dtl.DTLVardef@10b57a6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsTAF15 is upregulated in prefrontal cortex neurons of patients with FTD and ALS across different subtypes. Elevated TAF15 expression provokes ROS elevation, leading to neurotoxicity and gliosis. Neuronal TAF15 overexpression in the mouse mPFC results in FTD-like anxiety and impaired fear-memory phenotype. Reducing oxidative stress can rescue FTD-like phenotype caused by TAF15 upregulation.