Abstract Details

Title Early biochemical changes in a-synuclein in the central and enteric nervous system in Parkinson’s disease

Topic Movement Disorders

Presentation(s) P13 - Poster Session 13 (8:00 AM-9:00 AM)

Poster/Presentation
Number 5-004

Objective To understand whether early biochemical changes in α-Synuclein (αSyn) can be detected in the gut in Parkinson’s disease (PD) using a novel mouse model and human tissue.

Background

αSyn aggregates are the main components of Lewy bodies found in both the brain and the enteric nervous system of PD patients. Pathological changes and accompanying neurodegeneration precede diagnosis by years, with gastrointestinal symptoms among the earliest prodromal symptoms of PD, pointing to the gut as a potential starting point for pathology.

Design/Methods We hypothesize that biochemical changes in αSyn occur first in the gut, and are a marker of early pathology. We first characterized motor and gastrointestinal function in a mouse model expressing human αSyn under all its regulatory elements, thus enabling human-like spatiotemporal expression of αSyn that does not rely on overexpression, allowing for detection of early, disease-causing changes. We also examined expression of αSyn in the brain and gut in these mice, as well as in post-mortem brain tissue and colon tissue collected during routine screening colonoscopy in subjects with PD.

Results We show that our mouse model demonstrates typical motor impairments, as well as impairments of gastrointestinal function. It has previously been shown that membrane-bound αSyn is protected from aggregation, while cytosolic, soluble αSyn has a propensity to aggregate. We show reduced membrane-binding of αSyn in brain and gut in our mouse model as well as in post-mortem PD cortex. In preliminary results from human PD gut tissue obtained during routine screening colonoscopy, compared to healthy controls, we see a trend towards increased membrane-binding of αSyn in the colon.

Conclusions Changes in αSyn membrane-binding can be detected in mouse and human gut tissue. This study represents the first biochemical assessment of αSyn in the gut, and suggests that biochemical changes in αSyn in the gut can serve as a biomarker of disease.

Authors/Disclosures
Virginia Gao, MD PRESENTER	Dr. Gao has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Claire Henchcliffe, MD, PhD, FAAN (University of California, Irvine)	Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AskBio. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson & Johnson. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tolmar. Dr. Henchcliffe has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Savanna. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Meira GTx. Dr. Henchcliffe has or had stock in Axent Biosciences Inc. The institution of Dr. Henchcliffe has received research support from Weston Brain Institute. The institution of Dr. Henchcliffe has received research support from Blue Rock Therapeutics. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Parkinson Study Group. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Speaker/Course director with AAN. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Cleveland Clinic Foundation. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Vertex. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Speaker with ESGCT.
Andrea P. Lee, MD (Kansas University Medical Center)	Dr. Lee has nothing to disclose.
	No disclosure on file

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