Study Rationale:
The spread of alpha-synuclein (sticky protein that clumps in the brains of those with Parkinson's) occurs through a cell-to-cell prion-like (spreading) mechanism. Disrupting the cellular uptake of toxic alpha-synuclein fibrils (insoluble structures) can potentially slow the spread of alpha-synuclein pathology. Recent work out of Dr. Ted Dawson's research group implicated the Lymphocyte-activation gene 3 (regulates white blood cells; Lag3) as one of the receptors (proteins that receive signals for the cell) capable of binding and internalizing alpha-synuclein fibrils. This project will develop a biosensor (uses biological molecules to detect chemicals) that monitors Lag3-alpha-synuclein fibril interactions for use in screens of small molecule libraries to identify novel inhibitors for Lag3-alpha-synuclein fibril interactions.
Hypothesis:
This study will lay the foundation for a therapeutic discovery pipeline that leverages our fluorescence resonance energy transfer (measures the transfer of energy between molecules; FRET)-based cellular biosensor platform for the discovery of novel therapeutic leads that disrupt protein-protein interactions at the core of Parkinson's disease (PD) pathology.
Study Design:
In this study, we will develop a cell-based FRET biosensor expressing the Lag3 protein. Using very sensitive technology, developed by Flourescence Innovations, we will monitor energy measures and FRET efficiencies between Lag3 and alpha-synuclein fibrils. Our goal is to conduct pilot screens with the National Institutes of Health Clinical Compound library and the Library of Pharmacologically Active Compounds once our biosensor is optimized.
Impact on Diagnosis/Treatment of Parkinson's disease:
This project will contribute to two key areas of PD research. First, we will establish a novel platform to measure pathological protein-protein interactions in PD. Second, we will validate the recent identification of Lag3 as a target for therapeutic intervention in the spread of alpha-synuclein.
Next Steps for Development:
Future work from this study will involve screening larger, more diverse libraries. From there, we will move to testing compounds in pre-clinical models of PD.