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The effect of copper chelators on Zn(-) Superoxide Dismutase

The effect of copper chelators on Zn(-) Superoxide Dismutase. Lucy Brennan Dr. Joe Beckman Dr. Kari Trumbull. Amyotrophic Lateral Sclerosis. Motor neuron disease characterized by progressive paralysis 10% of cases are familial Mutations in SOD account for up to 7% of fALS.

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The effect of copper chelators on Zn(-) Superoxide Dismutase

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  1. The effect of copper chelators on Zn(-) Superoxide Dismutase Lucy Brennan Dr. Joe Beckman Dr. Kari Trumbull

  2. Amyotrophic Lateral Sclerosis • Motor neuron disease characterized by progressive paralysis • 10% of cases are familial • Mutations in SOD account for up to 7% of fALS

  3. Superoxide dismutase • (Cu2+ Zn)SOD+O2---> (Cu1+ Zn)SOD+O2 (Cu1+ Zn)SOD +O2-+2H+--> (Cu2+ Zn)SOD+H2O2 • Mutations linked to structural instability • Zn(-)SOD has a toxic gain of function believed to underlie fALS • (Cu1+)SOD +O2--> (Cu2+)SOD+ 02-

  4. Copper chelators • Dimercaptrol (BAL) • treatment for heavy metal toxicity and Wilson’s disease • Sulfhydral complex

  5. Goals Validation of WST assay To find a Cu-chelator that effectively removes copper from SOD Modifying the Cu-chelator into a potential drug for ALS

  6. WST assay

  7. Superoxide detection • An assay including potassium superoxide and WST-1 was performed • Addition of KO2- was added to the assay • WST has been reduced

  8. Xanthine assay • WST-1 + Xanthine and Xanthine oxidase • An increased absorbance was noted, indicating that WST-1 is reacting with superoxide

  9. Addition of BAL with Zn(-)SOD

  10. Implications • Validation of WST assay • Limitations • Insight into activity of Zn(-)SOD • Possible chelation therapy for ALS • Viable test for such compounds

  11. Acknowledgements • HHMI • Kevin Ahern • Dr. Joe Beckman • Dr. Kari Trumbull

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