title: TDP-43 modification in the hSOD1(G93A) amyotrophic lateral sclerosis mouse model.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult onset disease that produces gradual motor neuron cell death in the spinal cord (SP). Recently, transactive response DNA-binding protein 43 kDa (TDP-43), a critical component of insoluble ubiquitinated inclusions, has received attention in the treatment of neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD) and ALS. TDP-43 modifications, including hyperphosphorylation, truncation, and ubiquitination, have been reported in the pathogenesis of neurodegenerative diseases (NDs). However, the pathogenic mechanism of TDP-43 in ALS is unclear. To determine the association between TDP-43 and neurotoxicity in an ALS model, we characterized TDP-43 expression in hSOD1(G93A) transgenic mice (Tg) as an ALS animal model. TDP-43 was expressed by astrocytes and microglial cells in the SP of hSOD1(G93A) transgenic mice. In addition, the expression of phosphorylated and truncated TDP-43 increased in the SP of ALS mice compared with age-matched non-Tg. Furthermore, the serum iron concentration and expression of transferrin, a homeostasis-related iron protein, in the SP were increased relative to non-Tg. The protein expression level of HO-1 related to oxidative stress was increased in the SP of hSOD1(G93A) Tg relative to non-Tg. We show that an increase of TDP-43 modification, including phosphorylation or truncation, associates with dysfunctional iron homeostasis and an increase in oxidative stress in the SP of symptomatic hSOD1(G93A) Tg. These findings suggest that modified TDP-43 may be involved in motor neuron death in the SP of a SOD1(G93A)-expressing familial ALS (fALS) animal model.
authors.forename: MuDan
authors.initials: M
authors.lastname: Cai
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Choi
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Yang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014168:Transferrin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051547:Heme Oxygenase-1; D007501:Iron; D008565:Membrane Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014168:Transferrin; C000606290:SOD1 protein, human; C578077:Tardbp protein, mouse; C496542:Hmox1 protein, mouse; C000606291:Sod1 protein, mouse
keywords: Iron homeostasis; Motor neuron,; TDP-43,; hSOD1G93A,