A TDP-43 acetylation-mimic mutation that disrupts RNA-binding drives FTLD-like neurodegeneration in a mouse model of sporadic TDP-43 proteinopathy

Abstract TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis are neurodegenerative disorders characterized by aggregation and mislocalization of TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated TDP-43 foci and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell-derived neurons. Mice harboring the TDP-43K145Q mutation recapitulate key hallmarks of FTLD-TDP, including progressive TDP-43 phosphorylation and insolubility, mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study suggests that TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes, many of which modulate synaptic plasticity and stress response signaling. Unraveling this neurodegenerative cascade provides a new paradigm to interrogate FTLD pathogenesis.