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.
Keywords: Iron homeostasis; Motor neuron,; TDP-43,; hSOD1G93A,.