학술논문
RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.
Document Type
Academic Journal
Author
Necarsulmer JC; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, United States.; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Simon JM; UNC Neuroscience Center, University of North Carolina, Chapel Hill, United States.; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, United States.; Department of Genetics, University of North Carolina, Chapel Hill, United States.; Evangelista BA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, United States.; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Chen Y; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Tian X; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Nafees S; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Marquez AB; Human Pluripotent Stem Cell Core, University of North Carolina, Chapel Hill, United States.; Jiang H; Department of Biostatistics, University of North Carolina, Chapel Hill, United States.; Wang P; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Ajit D; Department of Neurology, University of North Carolina, Chapel Hill, United States.; Nikolova VD; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, United States.; Department of Psychiatry, The University of North Carolina, Chapel Hill, United States.; Harper KM; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, United States.; Department of Psychiatry, The University of North Carolina, Chapel Hill, United States.; Ezzell JA; Department of Cell Biology & Physiology, Histology Research Core Facility, University of North Carolina, Chapel Hill, United States.; Lin FC; Department of Biostatistics, University of North Carolina, Chapel Hill, United States.; Beltran AS; Department of Genetics, University of North Carolina, Chapel Hill, United States.; Human Pluripotent Stem Cell Core, University of North Carolina, Chapel Hill, United States.; Department of Pharmacology, University of North Carolina, Chapel Hill, United States.; Moy SS; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, United States.; Department of Psychiatry, The University of North Carolina, Chapel Hill, United States.; Cohen TJ; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, United States.; Department of Neurology, University of North Carolina, Chapel Hill, United States.; UNC Neuroscience Center, University of North Carolina, Chapel Hill, United States.; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, United States.
Source
Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
Subject
Language
English
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-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.
Competing Interests: JN, JS, BE, YC, XT, SN, AM, HJ, PW, DA, VN, KH, JE, FL, AB, SM, TC No competing interests declared
(© 2023, Necarsulmer et al.)
Competing Interests: JN, JS, BE, YC, XT, SN, AM, HJ, PW, DA, VN, KH, JE, FL, AB, SM, TC No competing interests declared
(© 2023, Necarsulmer et al.)