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

Autor: Julie C Necarsulmer, Jeremy M Simon, Baggio A Evangelista, Youjun Chen, Xu Tian, Sara Nafees, Ariana B Marquez, Huijun Jiang, Ping Wang, Deepa Ajit, Viktoriya D Nikolova, Kathryn M Harper, J Ashley Ezzell, Feng-Chang Lin, Adriana S Beltran, Sheryl S Moy, Todd J Cohen
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: eLife, Vol 12 (2023)
Druh dokumentu: article
ISSN: 2050-084X
DOI: 10.7554/eLife.85921
Popis: TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models 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 nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.
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