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

Elife. 2023 Oct 11:12:RP85921. doi: 10.7554/eLife.85921.


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.

Keywords: TDP-43; cell biology; human; mouse; mouse model; neurodegeneration; neuroscience; proteinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Animals
  • Cognitive Dysfunction*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Lobar Degeneration* / genetics
  • Frontotemporal Lobar Degeneration* / metabolism
  • Humans
  • Mice
  • RNA
  • TDP-43 Proteinopathies* / genetics
  • TDP-43 Proteinopathies* / metabolism


  • DNA-Binding Proteins
  • RNA
  • TDP-43 protein, mouse

Associated data

  • GEO/GSE216294
  • GEO/GSE163122
  • GEO/GSE27218