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

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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

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