RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 11, 2023
- Source ID
- 10.7554/elife.85921.3
Entities
People
- Adriana S Beltran
- Ariana B Marquez
- Baggio A Evangelista
- Deepa Ajit
- Feng-chang Lin
- Huijun Jiang
- J Ashley Ezzell
- Jeremy M Simon
- Julie Necarsulmer
- Kathryn M Harper
- Ping Wang
- Sara Nafees
- Sheryl S. Moy
- Todd J Cohen
- Viktoriya D. Nikolova
- Xu Tian
- Youjun Chen
Organizations
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Muscular Dystrophy Association
- National Center for Advancing Translational Sciences
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- United States Department of Defense
- University of North Carolina at Chapel Hill