Evaluation of PD-linked Transcripts in PPMI
MJFF Research Grant, 2012
Confirm associations between the expression of three susceptibility genes and Parkinsonís in peripheral blood of individuals with early-stage, untreated disease, and evaluate their potential usefulness as clinical biomarkers.
We will perform a cross-sectional, case-control study of 210 de novo cases with Parkinsonís disease and 150 age- and sex-matched controls enrolled in the Parkinson Progression Marker Initiative (PPMI). Specific transcript isoforms expressed from the three genetic loci will be assayed in human blood in a high-precision gene expression assay that directly measures RNA counts without bias from reverse transcription into cDNA. This technology uses molecular "barcodes" and single molecule imaging to detect and digitally count transcripts.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:†††††††††††††††††††††
There is a desperate need to measure Parkinsonís disease processes directly in a specific patient during life, unconfounded by symptomatic treatments. While inherited genetic risk profiles are static (same in a healthy newborn and at the onset of motor PD), molecular markers will be progressive and integrate epigenetic (from aging and environmental exposures) as well as genetic risks. Molecular markers should be precise, robust, and easy to measure in clinical laboratories, preferably in accessible body fluids such as blood or cerebrospinal fluid.
This study will confirm or refute associations between the peripheral expression of three PD genes and de novo PD. Replicated transcript associations can be further developed into clinical biomarkers that may be useful for accelerating the development of novel therapeutics.
In this study, we aimed to confirm associations between Parkinson's disease (PD) and protein production from three Parkinson's-linked genes. We also aimed to evaluate a potential usefulness of the protein production as a biomarker, an objective measure of disease that are crucial missing links in the development of therapies for PD. To accomplish this goal, we tested blood samples from individuals with early-stage, untreated disease enrolled in the Parkinson's Progression Markers Initiative (PPMI), The Michael J. Fox Foundation's landmark clinical study to find biomarkers. We found that the level of alpha-synuclein mRNA -- a molecule that serves as a template for protein production -- is lower in the blood of people with PD than that in healthy people. While this finding is not new, we were excited to confirm it in a large study like PPMI because this supports its relevance to a real-world clinical practice.
Head of the Neurogenomics Lab and the Parkinson Personalized Medicine Initiative at Harvard and Brigham and Womenís Hospital
Associate Professor of Neurology at Harvard Medical School
Location: Boston, Massachusetts, United States