Biochemical properties and in vivo effects of the SOD1 zinc-binding site mutant (H80G)

Marjatta Son, Uma Srikanth, Krishna Puttaparthi, Christina Luther, Jeffrey L. Elliott

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)891-901
Number of pages11
JournalJournal of Neurochemistry
Volume118
Issue number5
DOIs
StatePublished - Sep 1 2011

Keywords

  • amyotrophic lateral sclerosis
  • copper
  • inclusions
  • mitochondria
  • motor neuron
  • superoxide dismutase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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