Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology

TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. However, in human brains affected by Amyotrophic Lateral Sclerosis (ALS) or other pathological conditions, TDP-43 is often mislocalized in the cytoplasm, forming cytoplasmic inclusions. Existing TDP-43 transgenic mouse models have generally failed to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, limiting the study of cytoplasmic TDP-43 pathology. In the current study, we developed a transgenic mouse model that expresses the human CASP4 and replicates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner.