This grant builds upon the research from a prior grant: Interrogating LRRK2 Variants Common in Asian Populations to Discover Unique Biomarkers for Parkinson’s Disease
Study Rationale:
Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease (PD). Most research has focused on the LRRK2 G2019S mutation seen in Caucasians, and knowledge regarding LRRK2 variants occurring frequently in Asians with PD (G2385R and R1628P) remains scarce. Our project will advance understanding of LRRK2 Asian variants and will, we hope, contribute to finding better markers of diagnosing, monitoring and treating PD, particularly in regions of the world that are underrepresented in PD research.
Hypothesis:
We hypothesize that G2385R and R1628P carriers carry distinct body fluid biomarkers compared to non-carriers, due to the differential effects of these variants on a variety of cellular processes and bodily (e.g., immune and gastrointestinal system) functions. We also hypothesize that these biomarkers correlate with clinical phenotype and severity in PD.
Study Design:
Since 2020, our team has been carefully collecting detailed clinical data and biosamples (blood, urine and stools) from Malaysian patients with PD harboring G2385R and R1628P. For this project, we will collaborate with established laboratories in Europe and the USA to analyze these samples, aiming to identify biomarkers associated with G2385R and R1628P. We will investigate their LRRK2 kinase (cell enzyme) activities. And explore whether, and how, these variants interact with the immune system, the lysosomal system (responsible for the “garbage disposal” in our cells), as well as gut inflammation and metabolism - processes now thought to be highly relevant to the development of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease:
LRRK2 is an especially relevant area of study given the advent of LRRK2 kinase inhibitors for human use (a promising new class of genetics-based treatment for PD). This multinational collaboration between PD neurologists and scientists in Asia, and MJFF-supported scientists in Europe and the USA with proven track records in LRRK2 research, will be an important addition to current global biomarker initiatives.
Next Steps for Development:
Besides promoting diversity, equity and inclusion in the PD field, this team science effort with sharing of critical knowledge and skills will enable Malaysian researchers to conduct experiments locally as part of future discovery efforts within the MJFF LRRK2 consortium and contribute to clinical trials of LRRK-directed therapies.