Academic Journal
RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy
| العنوان: | RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy |
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| المؤلفون: | Necarsulmer, Julie C, Simon, Jeremy M, Evangelista, Baggio A, Chen, Youjun, Tian, Xu, Nafees, Sara, Marquez, Ariana B, Jiang, Huijun, Wang, Ping, Ajit, Deepa, Nikolova, Viktoriya D, Harper, Kathryn M, Ezzell, J Ashley, Lin, Feng-Chang, Beltran, Adriana S, Moy, Sheryl S, Cohen, Todd J |
| المساهمون: | National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging, National Institute of General Medical Sciences, Muscular Dystrophy Association, U.S. Department of Defense, National Center for Advancing Translational Sciences |
| المصدر: | eLife ; volume 12 ; ISSN 2050-084X |
| بيانات النشر: | eLife Sciences Publications, Ltd |
| سنة النشر: | 2023 |
| المجموعة: | eLife (E-Journal - via CrossRef) |
| الوصف: | 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-43 K145Q 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-43 K145Q 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.7554/elife.85921 |
| الاتاحة: | http://dx.doi.org/10.7554/elife.85921 https://cdn.elifesciences.org/articles/85921/elife-85921-v1.pdf https://cdn.elifesciences.org/articles/85921/elife-85921-v1.xml https://elifesciences.org/articles/85921 |
| Rights: | http://creativecommons.org/licenses/by/4.0/ ; http://creativecommons.org/licenses/by/4.0/ ; http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.8DE0DBC6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.7554/elife.85921 |
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