RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

• DOI: 10.7554/elife.85921.2
• Publication Date: 2023-09-15T14:04:29Z
• Authors: Julie Necarsulmer; Jeremy Simon; Baggio Evangelista; Youjun Chen; Xu Tian; Sara Nafees; Ariana Marquez Go...; Huijun Jiang; Ping Wang; Deepa Ajit; Viktoriya Nikolova; Kathryn Harper; Jennifer Ezzell; Feng-Chang Lin; Adriana Beltran; Sheryl Moy; Todd Cohen
• Keywords: Frontotemporal lobar degeneration; Cognitive Decline

TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation mislocalization of the nucleic-acid binding protein subsequent neuronal dysfunction. Here, we developed endogenous models sporadic proteinopathy based on principle that disease-associated acetylation at lysine 145 (K145) alters conformation, impairs RNA-binding capacity, induces downstream mis-regulation target genes. Expression acetylation-mimic K145Q resulted in stress-induced nuclear foci loss function primary mouse human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring mutation recapitulated key hallmarks FTLD, progressive phosphorylation insolubility, mis-localization, transcriptomic splicing alterations, cognitive Our study supports a model which drives dysfunction decline through aberrant transcription critical genes regulate synaptic plasticity stress response signaling. The cascade initiated recapitulates many aspects FTLD provides new paradigm to further interrogate proteinopathies.