Nuclear TAR DNA Binding Protein 43 Expression in Spinal Cord Neurons Correlates With the Clinical Course in Amyotrophic Lateral Sclerosis

TAR DNA binding protein 43 (TDP-43) has been considered a signature protein in frontotemporal dementia and amyotrophic lateral sclerosis (ALS), but not in ALS associated with the superoxide dismutase 1 (SODI) gene mutations (ALSI). To clarify how TDP may be involved in ALS pathogenesis, clinical and pathological features in cases of sporadic ALS ([SALS] n = 18) and ALSI (n = 6) were analyzed. In SALS patients with rapid clinical courses. TDP mislocalization (i.e. cytoplasmic staining and TDP-Positive Cytoplasmic inclusions) in anterior horn cells was frequent. In SALS patients with slow clinical courses, TDP-43 mislocalization was rare. In an ALSI patient with the SODI gene mutation C111Y, there were numerous TDP-positive inclusions and colocalization of SODI and TDP. In mutant SODI transgenic (G93A) mice at the end stage (median, 256 days). TDP-positive inclusions and TDP colocahzation with SODI were also observed: nuclear TDP-43 immunoreactivity was highly correlated with life span in these mice. In both humans and mice, nuclei that stained strongly for TDP were large and circular weakly stained nuclei were atrophic or deformed. In conclusion. low levels of TDP expression in the nucleus cor relate with a rapid clinical course in SALS and in ALSI model mice, suggesting that nuclear TDP may play a protective role against motor neuron death resulting from different underlying etiologies.