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Effects of Cystamine, a Transglutaminase Inhibitor in a Mouse
Model of Progressive Supranuclear Palsy
Michael Zorniak
Department of Biology
Lake Forest College
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PathologyBackground
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
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Calcium
TGase
Tau Cross-linkingBackground
(CH2)2C
O
NH2
H2NCH2(CH2)3
(CH2)2C
O
N(CH2)4
H
+NH3
Adapted from Lorand et al., 2003
+
Soluble Insoluble
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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?
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Effects of Cystamine
NUCLEUS ER Ca2+ TGase
ROS
TAU
NEURONAL DEATH
Cross-link
P
?
Hypothesis
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Gaps in Knowledge
• Will cystamine have the same therapeutic effects in P301L mice as it did in HD mice?
Predictions:
Oxidative Stress Neuropathology Motor Behavior
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My Contribution
• Aim One: Determine levels of oxidative stress in P301L mice
• Aim Two: Treat P301L mice with cystamine and perform behavioral tests
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Results
220
97
66
45
30
42 kDaActin
3 minute
exposure
Human AD Tissue
MW +-AD
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AD Cont
rol
WT
Tau
P301
L
MW
Actin
3 minute
exposure
42 kDa
220120100
6080
504030
20
Results
11 11 11 10.5 14 14 12 12 4.3 4.3 13 ?Age (Months)
Mouse Tissue
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Aim 2: Effects of Cystamine
Water Treated
P301L Mice
Cystamine Treated
P301L Mice
Behavioral Tests
Harvest CNS Tissue
Methods
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Wire HangBehavioral Test
Normal Motor Disturbance
Methods
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Results
Average Monthly Wire Hang Times for P301L Mice
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Results
Average Monthly Consumption for P301L Mice
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Results
Average Monthly Weight Gain for P301L Mice
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Future Research
Water vs. Cystamine Treated P301L Mice
Discussion
Oxidative Stress
Neuropathology
Motor Behavior
Prediction Done Result
No Change
?
?
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Acknowledgements ASPETDr. Karie ScroginDr. Nancy A. MumaShanti FraustoNichole DudekYing Dai Ju ShiBozena Zemaitaitis
Funded by Society for Progressive Supranuclear Palsy