Objective: The goal is to measure α-Synuclein (αSyn) membrane-binding in the enteric and central nervous system in Parkinson’s disease (PD) using both a novel, humanized mouse model and human tissue.

Background: The physiological synaptic functions of αSyn are mediated by its membrane-binding region, and loss of membrane-binding leads to αSyn aggregation. 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. We hypothesize that changes in αSyn membrane-binding occur first in the gut and are a marker of early pathology.

Method: We characterized motor and gastrointestinal function in αSynBAC mice, which express 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 colon tissue collected during routine screening colonoscopy in subjects with PD and healthy controls.

Results: αSynBAC mice demonstrate typical motor impairments, as well as impairments of gastrointestinal motility. We 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.

Conclusion: Changes in αSyn membrane-binding can be detected in a mouse model of PD and in tissue from humans with PD. This study represents the first biochemical assessment of αSyn in the gut, and suggests that decreased αSyn membrane-binding can serve as an early biomarker of disease.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/decreased-%ce%b1-synuclein-membrane-binding-in-the-enteric-nervous-system-as-a-marker-of-early-pathology-in-parkinsons-disease/