Purine Biomarkers of LRRK2-Associated Parkinson's Disease
Research Grant, 2018
This grant builds upon the research from a prior grant:
Oxidative damage to brain cells - akin to rust on car parts - builds up in Parkinson's disease (PD) and leads to breakdown of brain functions. Urate is a natural antioxidant that can protect brain cells in the laboratory. In the blood and cerebrospinal fluid, which bathes the brain and spinal cord, urate can serve as an indicator (biomarker) of both reduced risk and slower progression of PD. We aim to find out whether urate and similar molecules, collectively known as purines, as well as the overall antioxidant capacity, might serve as biomarkers of protection against an inherited form of Parkinson's caused by changes (mutations) in the LRRK2 gene.
Blood samples from people with LRRK2-associated PD, people without PD but carrying the LRRK2 mutation (carriers) and people without PD or the mutation will be analyzed using validated laboratory measurements of purines and of total antioxidant capacity. If those are elevated in blood samples from people with LRRK2-associated Parkinson's, we will repeat the measurements in another set of blood samples and corresponding cerebrospinal fluid samples.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
If this study provides evidence that purines serve as biomarkers in LRRK2-associated PD just as they do in other types of PD, then purines may be studied further for their potential ability to predict Parkinson's risk in LRRK2 mutation carriers. Similarly, the mechanism by which any implicated purine(s) might interact with LRRK2 may be studied. Identifying a purine as a biomarker of LRRK2-associated PD could also reduce the number of participants needed for future clinical trials involving LRRK2 carriers or even suggest purine-elevating treatments as candidate strategies for Parkinson's disease prevention in LRRK2 mutation carriers.
We hypothesize that urate levels will be higher in people who do not have Parkinson's despite having the LRRK2 mutation, suggesting that urate may serve as a biomarker of protection against LRRK2-associated PD. Whereas the present study is based on a snapshot of PD status -- whether someone has PD at a given point in time -- future studies could directly test the predictive power of purines by following PD status over the years to determine, for example, whether LRRK2 mutation carriers with higher levels of urate develop Parkinson's disease later in life.
Professor of Neurology at Harvard Medical School
Director, Molecular Neurobiology Laboratory at Massachusetts General Hospital
Location: Boston, Massachusetts