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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., Soluble Insoluble
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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
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
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
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?
Effects of Cystamine
NUCLEUS ER Ca2+ TGase
ROS
TAU
NEURONAL DEATH
Cross-link
P
?
Hypothesis
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
My Contribution
• Aim One: Determine levels of oxidative stress in P301L mice
• Aim Two: Treat P301L mice with cystamine and perform behavioral tests
Results
220
97
66
45
30
42 kDaActin
3 minute
exposure
Human AD Tissue
MW +-AD
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
Aim 2: Effects of Cystamine
Water Treated
P301L Mice
Cystamine Treated
P301L Mice
Behavioral Tests
Harvest CNS Tissue
Methods
Wire HangBehavioral Test
Normal Motor Disturbance
Methods
Results
Average Monthly Wire Hang Times for P301L Mice
Results
Average Monthly Consumption for P301L Mice
Results
Average Monthly Weight Gain for P301L Mice
Future Research
Water vs. Cystamine Treated P301L Mice
Discussion
Oxidative Stress
Neuropathology
Motor Behavior
Prediction Done Result
No Change
?
?
Acknowledgements ASPETDr. Karie ScroginDr. Nancy A. MumaShanti FraustoNichole DudekYing Dai Ju ShiBozena Zemaitaitis
Funded by Society for Progressive Supranuclear Palsy