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Effects of Cystamine, a Transglutaminase Inhibitor in a Mouse Model of Progressive Supranuclear Palsy

Effects of Cystamine, a Transglutaminase Inhibitor in a Mouse Model of Progressive Supranuclear Palsy. Michael Zorniak Department of Biology Lake Forest College. Background. Pathology. PSP is a tauopathy Insoluble aggregates of tau in basal ganglia Transglutaminase cross-links tau

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Effects of Cystamine, a Transglutaminase Inhibitor in a Mouse Model of Progressive Supranuclear Palsy

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  1. Effects of Cystamine, a Transglutaminase Inhibitor in a Mouse Model of Progressive Supranuclear Palsy Michael Zorniak Department of Biology Lake Forest College

  2. Background Pathology • PSP is a tauopathy • Insoluble aggregates of tau in basal ganglia • Transglutaminase cross-links tau • Oxidative stress http://www.pathology.vcu.edu/education/cns/lab1.c.html

  3. Background Tau Cross-linking O (CH2)2C NH2 O TGase (CH2)2C N(CH2)4 + Calcium H H2NCH2(CH2)3 +NH3 Insoluble Soluble Adapted from Lorand et al., 2003

  4. Huntingtin Disease mice Transglutaminase cross-links huntingtin Transglutaminase enzyme activity is increased Treated with TGase inhibitor cystamine P301L tau transgenic mice Transglutaminase cross-links phosphorylated tau Transglutaminase enzyme activity elevated Cystamine treatment? Background Previous Investigations Dedeoglu et al., 2002 Halverson et al., 2005

  5. Hypothesis Effects of Cystamine ROS NEURONAL DEATH ER Ca2+ TGase NUCLEUS ? Cross-link P TAU

  6. Gaps in Knowledge • Will cystamine have the same therapeutic effects in P301L mice as it did in HD mice? Predictions: Motor Behavior Oxidative Stress Neuropathology

  7. My Contribution • Aim One: Determine levels of oxidative stress in P301L mice • Aim Two: Treat P301L mice with cystamine and perform behavioral tests

  8. Results Human AD Tissue AD - + MW 220 97 66 3 minute exposure 45 30 Actin 42 kDa

  9. Results Mouse Tissue AD Control P301L WT Tau MW 220 120 100 80 3 minute exposure 60 50 40 30 20 Age (Months) 11 11 11 10.5 14 14 12 12 4.3 4.3 13 ? 42 kDa Actin

  10. Methods Aim 2: Effects of Cystamine Water Treated P301L Mice Cystamine Treated P301L Mice Behavioral Tests Harvest CNS Tissue

  11. Methods Wire HangBehavioral Test Motor Disturbance Normal

  12. Results Average Monthly Wire Hang Times for P301L Mice

  13. Results Average Monthly Consumption for P301L Mice

  14. Results Average Monthly Weight Gain for P301L Mice

  15. Discussion Future Research Water vs. Cystamine Treated P301L Mice Prediction Done Result No Change Motor Behavior ? Oxidative Stress ? Neuropathology

  16. Acknowledgements ASPET Dr. Karie Scrogin Dr. Nancy A. Muma Shanti Frausto Nichole Dudek Ying Dai Ju Shi Bozena Zemaitaitis Funded by Society for Progressive Supranuclear Palsy

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