Abstract Details

Title The Source and Pathogenic Potential of Blood-derived Alpha-Synuclein

Topic Movement Disorders

Presentation(s) S4 - Movement Disorders: Basic Science (2:48 PM-3:00 PM)

Poster/Presentation
Number 010

Objective

This study investigates the source and pathogenic potential of blood-based alpha-synuclein (aSyn) using conformation-selective antibodies.

Background Monoclonal antibodies raised against different conformations or “strains” of recombinant aSyn have been shown to recognize differential but overlapping subsets of Lewy brain pathology. These antibodies can also recognize aSyn conformations enriched in blood that differentiate individuals with Parkinson’s disease (PD) from dementia with Lewy bodies and that correlate with rates of cognitive decline in PD. The source and pathologic potential of these species remain uncharacterized.

Design/Methods

To investigate the source of these aSyn conformations in blood, we measured levels by strain-selective ELISA in blood cells and in plasma fractions separated by size exclusion chromatography. Concurrently, we applied these blood-derived aSyn strains to seed amplification assays (SAAs) and in vitro cellular models to test their pathogenic potential.

Results In blood, the aSyn conformation identified by these strain-selective antibodies are most enriched in fractions that correlate with extracellular vesicles. Plasma aSyn strain levels do not correlate with levels in blood cells. In SAA, aggregation of monomeric aSyn was induced by plasma derived aSyn in a strain-selective and a disease-specific manner. Cellular models also reflected a strain-selective induction of aSyn pathology.

Conclusions Overall, these strain-selective antibodies that correlate with cognitive status and trajectory in Lewy body disease are enriched in blood-derived extracellular vesicles and have pathogenic properties when tested in SAA and in vitro cellular models. These aSyn conformations outside of the brain could serve as disease biomarkers and lead to a better understanding of the origin and spread of pathogenic aSyn pathology.

Authors/Disclosures
George Kannarkat PRESENTER	Dr. Kannarkat has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global.
Caroline A. Lewis	Ms. Lewis has nothing to disclose.
Robert Skrinak	No disclosure on file
Travis Unger	Mr. Unger has nothing to disclose.
Rebecca Zack	Rebecca Zack has nothing to disclose.
Thomas F. Tropea, DO (University of Pennsylvania)	Dr. Tropea has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bial. The institution of Dr. Tropea has received research support from NINDS. The institution of Dr. Tropea has received research support from Parkinson Foundation. The institution of Dr. Tropea has received research support from Michael J Fox Foundation.
Tal Gilboa	No disclosure on file
Kelvin Luk (University of Pennsylvania)	The institution of Kelvin Luk has received research support from National Institutes of Health. The institution of Kelvin Luk has received research support from Michael J. Fox Foundation. The institution of Kelvin Luk has received research support from Teva Pharmaceuticals.
Dmitry Ter-Ovanesyan, PhD	Dr. Ter-Ovanesyan has received intellectual property interests from a discovery or technology relating to health care.
Virginia Lee, PhD (University of Pennsylvania)	Virginia Lee, PhD has nothing to disclose.
David R. Walt, PhD	No disclosure on file
Alice Chen-Plotkin, MD	Dr. Chen-Plotkin has received intellectual property interests from a discovery or technology relating to health care.

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