This is an in vivo mouse model of TDP-43 proteinopathy that captures key features of human neurodegenerative disease, particularly Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The model targets a disease-relevant disruption in TDP-43’s interaction with cytoplasmic translational machinery, causing a cascade of human-like TDP-43 proteinopathy in vivo. Importantly, although the genetic change is systemic, pathological and degenerative changes are confined to the central nervous system, revealing a novel observation about the CNS’s intrinsic susceptibility to cytoplasmic TDP-43 dysfunction. Background: Current animal models, whether transgenic or knock-in, have failed to produce robust TDP-43 inclusion, glial pathology, and progressive neurodegeneration. Despite over a decade of intense effort, no existing TDP-43 mouse model has fully captured the pathological and functional hallmarks of human TDP-43 proteinopathies. This urgent need has limited the neurodegeneration field to define TDP-43 pathogenic mechanisms and develop effective therapeutics. Applications:
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