title: Biochemical properties and in vivo effects of the SOD1 zinc-binding site mutant (H80G).
abstract: This study presents the initial characterization of transgenic mice with mutations in a primary zinc-binding residue (H80), either alone or with a G93A mutation. H80G;G93A superoxide dismutase 1 (SOD1) transgenic mice developed paralysis with motor neuron loss, and ubiquitin inclusion-type rather than mitochondrial vacuolar pathology. Unlike G93A SOD1-related disease, the course was not accelerated by over-expression of copper chaperone for SOD1. H80G SOD1 transgenic mice did not manifest disease at levels of SOD1 transgene expressed. The H80G mutation altered certain biochemical parameters of both human wild-type SOD1 and G93A SOD1. The H80G mutation does not substantially change the age-dependent accumulation of G93A SOD1 aggregates and hydrophobic species in spinal cord. However, both H80G;G93A SOD1 and H80G SOD1 lack dismutase activity, the ability to form homodimers, and co-operativity with copper chaperone for SOD1, indicating that their dimerization interface is abnormal. The H80G mutation also made SOD1 susceptible to protease digestion. The H80G mutation alters the redox properties of SOD1. G93A SOD1 exists in either reduced or oxidized form, whereas H80G;G93A SOD1 and H80G SOD1 exist only in a reduced state. The inability of SOD1 with an H80G mutation to take part in normal oxidation-reduction reactions has important ramifications for disease mechanisms and pathology in vivo.
authors.affiliation: Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Marjatta
authors.initials: M
authors.lastname: Son
authors.forename: Uma
authors.initials: U
authors.lastname: Srikanth
authors.forename: Krishna
authors.initials: K
authors.lastname: Puttaparthi
authors.forename: Christina
authors.initials: C
authors.lastname: Luther
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Elliott
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016500:Color Therapy / Q000379:methods; D004195:Disease Models, Animal; D019286:Endopeptidase K / Q000494:pharmacology; D005973:Glutamine / Q000235:genetics*; D006639:Histidine / Q000235:genetics*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015032:Zinc / Q000378:metabolism*
chemical_list: C000606290:SOD1 protein, human; D005973:Glutamine; D006639:Histidine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019286:Endopeptidase K; D015032:Zinc