title: Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, a fatal degenerative disorder in which motor neurons in the central nervous system (CNS) progressively deteriorate. Most cases of ALS are sporadic, but 10% are familial and mutations affecting the copper (Cu)-dependent antioxidant Cu/Zn-superoxide dismutase (SOD1) are the most common familial cause. Cu malfunction is evident in CNS tissue from transgenic mice that over-express mutant SOD1 and modulating Cu bioavailability in the CNS provides positive therapeutic outcomes. In the present study we assessed levels of Cu and Zn, SOD activity, and SOD1 protein levels in CNS and non-CNS tissue from transgenic mutant SOD1 mice (SOD1(G37R)) and non-transgenic controls. Physiological SOD1 binds one structural Zn and one catalytic Cu per subunit. Due to over-expression of the transgene, SOD activity and SOD1 protein levels are elevated in all tissues examined from the SOD1(G37R) mice and a commensurate increase in Zn is evident. There is a comparable increase in Cu in non-CNS tissue, but the increase in Cu in the SOD1(G37R) mouse brain is limited and there is no increase in Cu in the spinal cord. The limited change in CNS Cu is associated with a strong disparity between SOD1 protein and SOD activity in the brain and spinal cord. We hypothesise that the limited capacity for CNS tissue to respond to an increased requirement for bioavailable Cu contributes to CNS vulnerability in ALS.
authors.affiliation: Department of Pathology, the University of Melbourne, Victoria 3010, Australia. pjcrouch@unimelb.edu.au.
authors.forename: J B
authors.initials: JB
authors.lastname: Hilton
authors.forename: A R
authors.initials: AR
authors.lastname: White
authors.forename: P J
authors.initials: PJ
authors.lastname: Crouch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003300:Copper / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D000072105:Superoxide Dismutase-1 / Q000502:physiology*
chemical_list: D003300:Copper; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1