Abstract
<h3>Objective:</h3> The goal is to understand whether changes in α-Synuclein (αSyn) membrane-binding can be detected in the enteric nervous system in Parkinson’s disease (PD) using a novel mouse model and human tissue. <h3>Background:</h3> αSyn aggregates are the main components of Lewy bodies found in both the brain and in the enteric nervous system of PD patients. Pathological changes and accompanying neurodegeneration precede diagnosis by years, with changes in gastrointestinal motility among the earliest prodromal symptoms of PD, pointing to the gut as a potential starting point for pathology. <h3>Design/Methods:</h3> We hypothesize that changes in αSyn membrane-binding occur first in the gut, and are a marker of early pathology. We 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. 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. <h3>Results:</h3> We showed that our mouse model demonstrates typical motor impairments, as well as impairments of gastrointestinal motility. We previously demonstrated that membrane-bound αSyn is protected from aggregation, while cytosolic, soluble αSyn has a propensity to aggregate. We now show reduced membrane-binding of αSyn in brain and gut in our mouse model as well as in PD cortex. In preliminary results from human PD gut tissue, compared to healthy controls, we see a trend towards decreased membrane-binding of αSyn in the colon as well as changes in post-translational modifications that are known to affect membrane-binding. <h3>Conclusions:</h3> Changes in in αSyn membrane-binding can be detected in mouse and human tissue. This study represents the first biochemical assessment of αSyn in the gut, and suggests that changes in αSyn membrane-binding can serve as a biomarker of disease. <b>Disclosure:</b> Dr. Gao has nothing to disclose. Mr. Briano has nothing to disclose. Ms. Komer has nothing to disclose. Dr. Crawford has received personal compensation for serving as an employee of seres. Dr. Crawford has received personal compensation for serving as an employee of merck. Dr. Crawford has received personal compensation for serving as an employee of ferring. Dr. Crawford has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for seres. Dr. Crawford has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ferring. Dr. Crawford has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for seres. Dr. Crawford has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for merck. Dr. Crawford has received stock or an ownership interest from seres. Dr. Crawford has received intellectual property interests from a discovery or technology relating to health care. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal. Dr. Henchcliffe has received personal compensation in the range of $0-$499 for serving as a Consultant for MedExcelCap. Dr. Henchcliffe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer. Dr. Henchcliffe has 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. Lee has nothing to disclose. Prof. Burré has received research support from NIH. Prof. Burré has received research support from Michael J. Fox Foundation. Prof. Burré has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with NIH.
Published Version
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