Nonmotor symptoms of PD revealed in mice with reduced vesicular storage

1
Non-motor symptoms of PD revealed in mice with
reduced vesicular storage

• Tonya Taylor
• MSP Symposium
• May 29, 2009

2
Overview of Parkinsons Disease

• 2nd most common neurodegenerative disorder
• Characterized by degeneration of DA neurons in
  the SNpc, subsequent loss of DA in the striatum,
  and presence of Lewy bodies
• Caused by genetic and environmental factors
• Tremor, rigidity, postural instability,
  bradykinesia
• Anosmia, sleep disturbances, depression, GI
  dysfunction

3
Characterization of VMAT2 LO mice
Caudle, et al J. Neurosci 2007
4
VMAT2-deficient mice display widespread
reductions in monoamines at 12-15 months of age
Taylor, et al J. Neurosci in press
5
VMAT2-deficient animals display reduced TH/TrpH
expression and neurodegeneration at 24 months of
age
6

• Hypothesis Reduced monoamine storage results in
  altered neurotransmission leading to the
  development of symptoms associated with PD

7
VMAT2 LO animals display progressive deficits in
olfactory discrimination
Taylor, et al J. Neurosci in press
8
VMAT2 LO animals display normal circadian
activity but a premature shortened latency to
behavioral signs of sleep
Taylor, et al J. Neurosci in press
9
VMAT2 LO mice display altered gastric motility
Taylor, et al J. Neurosci in press
10
VMAT2 LO animals display an anxiety-like and a
progressive depressive-like phenotype
4-6 months
12-15 months
FST
TST
Taylor, et al J. Neurosci in press
11
VMAT2 LO mice exhibit motor deficits at older ages
12
Conclusions and Future Directions

• Reduced vesicular storage of monoamines
  reproduces many of the non-motor symptoms
  associated with PD
• at advanced ages, reproduces motor phenotype
• Potential model for therapeutic intervention for
  non-motor symptoms
• Antidepressant therapy?
• Monoamine precursors?

13
Acknowledgements

• Miller Lab
• Dr. Gary Miller
• Kennie Shepherd, PhD
• Jodi Watson, BSN, MS
• Minzheng Wang, MD
• Yingjie Li, MD
• Danielle Dean, MS
• Stephen Hasak, MPH
• David Kopp, MPH
• Dana Annerino
• Brian Wojeck
• Weinshenker Lab
• Dr. David Weinshenker
• Jesse Schank, PhD
• Heather Mitchell
• Greene Lab
• Dr. James Greene

• Iuvone Lab
• Dr. P. Michael Iuvone
• Nikita Pozdeyev, PhD
• Chad Jackson
• University of Washington
• W. Michael Caudle, PhD
• Committee Members
• Dr. James Greene
• Dr. Jason Hansen
• Dr. Yoland Smith
• Dr. David Weinshenker
• Funding
• NRSA F31 ES017247
• Emory Graduate Diversity Fellowship