Study Rationale: Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease (PD). Many studies have focused on the LRRK2 G2019S mutation found in Caucasians, and less is known about the LRRK2 variants that occur more frequently in Asians with PD (G2385R and R1628P). Our project will advance understanding of the LRRK2 Asian variants and will, we hope, lead to the discovery of better markers for diagnosing, monitoring and treating PD, particularly in regions of the world that are underrepresented in PD research.
Hypothesis: We hypothesize that individuals carrying the G2385R and R1628P variants of LRRK2 will display distinct biomarkers due to the different effects these variants have on cellular processes and systems, including the immune and gastrointestinal systems. We further hypothesize that these biomarkers will correlate with clinical phenotype and disease severity.
Study Design: Since 2020, our team has carefully collected detailed clinical data and biosamples (blood, urine and stools) from Malaysian individuals with PD who harbor the G2385R and R1628P variants. Now, we will collaborate with established laboratories in Europe and the U.S. to analyze these samples and identify associated biomarkers. We will investigate the activity of the LRRK2 kinase in these samples and explore whether, and how, these variants influence the immune system, the lysosomal system (responsible for removing damaged cell materials) and gut inflammation and metabolism — processes thought to be highly relevant to the development of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: Given the advent of promising new LRRK2-targeted PD therapeutics, LRRK2 is a particularly important area of study. Our multinational collaboration between PD neurologists and scientists in Asia, and MJFF-supported scientists in Europe and the U.S., will facilitate the global search for PD biomarkers.
Next Steps for Development: In addition to promoting diversity, equity and inclusion in PD research, this effort to share 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.