Aberrant hydrophobicity of mutant SODls: Implication for toxicity in Amyotrophic Lateral Sclerosis

Friday October 15
Chem. Sci. & Engineering Room 211
10:00 a.m.

Presenter: Dr. Ashutosh Tiwari, Michigan Technological Univ.Dept. of Chemistry

Abstract: More than 100 different mutations in the gene encoding Cu/Znsuperoxide dismutase (SODl) cause preferential motor neuron degeneration in familial amyotrophic lateral  sclerosis (ALS).  Although the cellular target(s) of mutant SODl toxicity have not been precisely specified, evidence to date suggests that altered conformations of mutant SODls trigger perturbations of cellular homeostasis that ultimately cause motor neuron degeneration.  My efforts have focused on identifying the underlying mechanism(s) by which mutant SODl proteins misfold or aggregate to produce toxicity.  My studies show that SODl proteins upon mutation are predisposed to loss of metal ion binding, destabilization, disulfide reduction, partial unfolding, and monomerization.  Overall, our findings support the notion that misfolding associated with metal deficiency may facilitate aberrant interactions of SODl with itself or with other cellular constituents and may thereby contribute to neuronal toxicity.

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