Study Rationale:
Parkinson's disease (PD) is associated with the presence of protein aggregates in the form of Lewy bodies composed of the protein alpha-synuclein. One of the greatest obstacles for developing a disease-modifying therapy for PD is the lack of early diagnosis. To date, there is no definite, sensitive and predictive laboratory test available that can identify individuals well before they show the clinical manifestation.
Hypothesis:
The main goal of this project is to develop a biochemical test to detect alpha-synuclein oligomers in cerebrospinal fluid (CSF).
Study Design:
Our strategy utilizes a cyclic amplification procedure (termed PMCA) to detect minute amounts of oligomers by exploiting the functional property of oligomers to catalyze the misfolding of protein. PMCA has been so far applied to the ultra-sensitive detection of misfolded oligomers of the prion protein implicated in prion diseases and amyloid-beta protein involved in Alzheimer's disease. This project aims to expand the PMCA concept to detect alpha-synuclein oligomers in CSF samples from PD patients. We will optimize the technology, evaluate its sensitivity and specificity for PD diagnosis, and analyze whether it can be used to monitor disease progression.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We expect that our project will lay the foundation for the development of a sensitive, noninvasive and objective laboratory test to detect alpha-synuclein oligomers in CSF of people affected by PD and related synucleinopathies. Such a technology might have tremendous impact on enabling the biochemical diagnosis of PD, perhaps pre-symptomatically. This is a major goal in the PD field, since it would enable therapeutic interventions early on, before substantial brain damage has yet occurred.
Next Steps for Development:
If successful, this project will provide proof-of-concept demonstration of the utility of PMCA for high sensitive detection of alpha-synuclein oligomers in CSF. Future studies should aim to analyze the large-scale performance and reproducibility of the assay across different laboratories as well as the adaptation of the methodology for detection in blood samples.