Title

Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis

UMMS Affiliation

Department of Neurology; Department of Molecular Genetics and Microbiology

Date

6-17-2005

Document Type

Article

Subjects

Amyotrophic Lateral Sclerosis; Animals; Cell Line, Tumor; Dithiothreitol; Humans; Hydrophobicity; Mice; *Mutation; Superoxide Dismutase

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

More than 100 different mutations in the gene encoding Cu,Zn-superoxide dismutase (SOD1) cause preferential motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS). Although the cellular target(s) of mutant SOD1 toxicity have not been precisely specified, evidence to date supports the hypothesis that ALS-related mutations may increase the burden of partially unfolded SOD1 species. Influences that may destabilize SOD1 in vivo include impaired metal ion binding, reduction of the intrasubunit disulfide bond, or oxidative modification. In this study, we observed that metal-deficient as-isolated SOD1 mutants (H46R, G85R, D124V, D125H, and S134N) with disordered electrostatic and zinc-binding loops exhibited aberrant binding to hydrophobic beads in the absence of other destabilizing agents. Other purified ALS-related mutants that can biologically incorporate nearly normal amounts of stabilizing zinc ions (A4V, L38V, G41S, D90A, and G93A) exhibited maximal hydrophobic behavior after exposure to both a disulfide reducing agent and a metal chelator, while normal SOD1 was more resistant to these agents. Moreover, we detected hydrophobic SOD1 species in lysates from affected tissues in G85R and G93A mutant but not wildtype SOD1 transgenic mice. These findings suggest that a susceptibility to the cellular disulfide reducing environment and zinc loss may convert otherwise stable SOD1 mutants into metal-deficient forms with locally destabilized electrostatic and zinc-binding loops. These abnormally hydrophobic SOD1 species may promote aberrant interactions of the enzyme with itself or with other cellular constituents to produce toxicity in familial ALS.

Rights and Permissions

Citation: J Biol Chem. 2005 Aug 19;280(33):29771-9. Epub 2005 Jun 15. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

15958382