| Autor: |
Julie Necarsulmer, Jeremy Simon, Baggio Evangelista, Youjun Chen, Xu Tian, Sara Nafees, Ariana Marquez Gonzalez, Ping Wang, Deepa Ajit, Viktoriya Nikolova, Kathryn Harper, Jennifer Ezzell, Adriana Beltran, Sheryl Moy, Todd Cohen |
| Rok vydání: |
2023 |
| DOI: |
10.7554/elife.85921 |
| Popis: |
TDP-43 proteinopathies including frontotemporal lobar dementia (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 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 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 FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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