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

Tonya TaylorMSP Symposium

May 29, 2009

Overview of Parkinson’s 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

Characterization of VMAT2 LO mice

Caudle, et al J. Neurosci 2007

VMAT2-deficient mice display widespread reductions in monoamines at 12-15 months of age

Taylor, et al J. Neurosci in press

VMAT2-deficient animals display reduced TH/TrpH expression and neurodegeneration at 24 months of age

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

VMAT2 LO animals display progressive deficits in olfactory discrimination

Taylor, et al J. Neurosci in press

VMAT2 LO animals display normal circadian activity but a premature shortened latency to behavioral signs of sleep

Taylor, et al J. Neurosci in press

VMAT2 LO mice display altered gastric motility

Taylor, et al J. Neurosci in press

VMAT2 LO animals display an anxiety-like and a progressive depressive-like phenotype

Taylor, et al J. Neurosci in press

4-6 months 12-15 months

FST

TST

VMAT2 LO mice exhibit motor deficits at older ages

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?

AcknowledgementsMiller LabDr. Gary MillerKennie Shepherd, PhDJodi Watson, BSN, MSMinzheng Wang, MDYingjie Li, MDDanielle Dean, MSStephen Hasak, MPHDavid Kopp, MPHDana AnnerinoBrian Wojeck

Weinshenker LabDr. David WeinshenkerJesse Schank, PhDHeather Mitchell

Greene LabDr. James GreeneAliReza Noorian, MD

Iuvone LabDr. P. Michael IuvoneNikita Pozdeyev, PhDChad Jackson

University of WashingtonW. Michael Caudle, PhD

Committee MembersDr. James GreeneDr. Jason HansenDr. Yoland SmithDr. David Weinshenker

FundingNRSA F31 ES017247Emory Graduate Diversity Fellowship