Mislocalization of TDP-43 in the G93A mutant SOD1 transgenic mouse model of ALS.

Previous evidence demonstrates that TAR DNA binding protein (TDP-43) mislocalization is a key pathological feature of amyotrophic lateral sclerosis (ALS). TDP-43 normally shows nuclear localization, but in CNS tissue from patients who died with ALS this protein mislocalizes to the cytoplasm. Disease specific TDP-43 species have also been reported to include hyperphosphorylated TDP-43, as well as a C-terminal fragment. Whether these abnormal TDP-43 features are present in patients with SOD1-related familial ALS (fALS), or in mutant SOD1 over-expressing transgenic mouse models of ALS remains controversial. Here we investigate TDP-43 pathology in transgenic mice expressing the G93A mutant form of SOD1. In contrast to previous reports we observe redistribution of TDP-43 to the cytoplasm of motor neurons in mutant SOD1 transgenic mice, but this is seen only in mice having advanced disease. Furthermore, we also observe rounded TDP-43 immunoreactive inclusions associated with intense ubiquitin immunoreactivity in lumbar spinal cord at end stage disease in mSOD mice. These data indicate that TDP-43 mislocalization and ubiquitination are present in end stage mSOD mice. However, we do not observe C-terminal TDP-43 fragments nor TDP-43 hyperphosphorylated species in these end stage mSOD mice. Our findings indicate that G93A mutant SOD1 transgenic mice recapitulate some key pathological, but not all biochemical hallmarks, of TDP-43 pathology previously observed in human ALS. These studies suggest motor neuron degeneration in the mutant SOD1 transgenic mice is associated with TDP-43 histopathology.