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 (SOD1) gene mutations (ALS1). To clarify how TDP may be involved in ALS pathogenesis, clinical and pathological features in cases of sporadic ALS ([SALS] n = 18) and ALS1 (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 ALS1 patient with the SOD1 gene mutation C111Y, there were numerous TDP-positive inclusions and colocalization of SOD1 and TDP. In mutant SOD1 transgenic (G93A) mice at the end stage (median, 256 days), TDP-positive inclusions and TDP colocalization with SOD1 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 ALS1 model mice, suggesting that nuclear TDP may play a protective role against motor neuron death resulting from different underlying etiologies.
Sumi
Hisae
H
Department of Neurology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Japan. hasumi@neurol.med.osaka-u.ac.jp
Kato
Shinsuke
S
Mochimaru
Yuko
Y
Fujimura
Harutoshi
H
Etoh
Masaki
M
Sakoda
Saburo
S
D000367:Age Factors; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1