RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.
Julie C NecarsulmerJeremy M SimonBaggio A EvangelistaYoujun ChenXu TianSara NafeesAriana B MarquezHuijun JiangPing WangDeepa AjitViktoriya D NikolovaKathryn M HarperJ Ashley EzzellFeng-Chang LinAdriana S BeltranSheryl S MoyTodd J CohenPublished in: eLife (2023)
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.
Keyphrases
- amyotrophic lateral sclerosis
- cognitive decline
- stem cells
- binding protein
- stress induced
- mouse model
- mild cognitive impairment
- nucleic acid
- endothelial cells
- poor prognosis
- spinal cord injury
- spinal cord
- metabolic syndrome
- brain injury
- insulin resistance
- subarachnoid hemorrhage
- molecular dynamics simulations
- cell therapy