Objective:

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. 

Background:

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. 

Design/Methods:

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.

Results:

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. 

Conclusions:

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.