Study Rationale:
Our Team’s research shows that special forms of α-synuclein protein extracted or amplified from biospecimen donations from people with Parkinson’s disease may hold different shapes and other features that may help explain why the disease is different in different people. We plan to use advanced tools like single-particle cryo-electron microscopy and mass spectrometry to study α-synuclein at the molecular level. This will help us develop more accurate tests that can predict how the disease will behave in each person and may also help us find new ways to treat Parkinson’s disease with better precision.
Hypothesis:
Our Team tests the hypothesis that conformational and biochemical diversity intrinsic to α-synuclein disease-associated seeds in Parkinson’s disease and related Lewy body disorders can be characterized to atomic resolutions that enable the development of new prognostic assays.
Study Design:
We have developed powerful methodologies that will identify essential factors and associated pathologies in the brain driving α-synuclein heterogeneities in disease. We will discover which disease phenotypes are associated with these different factors and pathologies in several of our deeply phenotyped longitudinal patient cohorts, and how these associations can inform the refinement of existing diagnostic assays into precision prognostic instruments.
Impact on Diagnosis/Treatment of Parkinson’s disease:
A better knowledge of how subtle variations in the protein α-synuclein might predict disease outcomes could be useful for future therapeutic approaches to ensure the right treatments get to the right patients at the right stage in disease.
Next Steps for Development:
In full alignment with best open science practices, our developed structural and proteomic datasets, as well as novel assay platforms, can be adopted by other laboratories around the world to explore new cohorts of patients in moving towards broad clinical application of our discoveries.