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

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

3. Calcium TGase Tau Cross-linking Background (CH 2 ) 2 C O NH 2 H 2 NCH 2 (CH 2 ) 3 (CH 2 ) 2 C O N(CH 2 ) 4 H +NH 3 Adapted from Lorand et al., 2003 + Soluble Insoluble

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

5. Effects of Cystamine NUCLEUS ER Ca 2+ TGase ROS TAU NEURONAL DEATH Cross-link P ? Hypothesis

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

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

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

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

11. Wire Hang Behavioral Test Normal Motor Disturbance Methods

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. Future Research Water vs. Cystamine Treated P301L Mice Discussion Oxidative Stress Neuropathology Motor Behavior PredictionDoneResult No Change ? ?

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