Study Rationale:
Leucine-rich repeat kinase 2 (LRRK2) is the greatest known genetic contributor to Parkinson's disease (PD). Research studies have linked mutations (changes) in the LRRK2 gene to DNA damage in mitochondria, powerhouses of the cell. Mitochondrial DNA (mtDNA) damage can be used for examining molecular mechanisms and screening therapeutic strategies for PD. However, while existing assays (experimental setups) provide total estimates of mtDNA damage, they cannot determine where exactly the mtDNA is damaged. The exact location of mtDNA damage could serve as a biomarker -- objective measure of Parkinson's disease -- useful in diagnosis and treatment evaluation.
Hypothesis:
To discover precision biomarkers of PD based on mtDNA damage and assist Parkinson's diagnosis as well as progression and treatment evaluation, we will develop a new assay for high-resolution damage mapping of mtDNA.
Study Design:
We will build on our unique expertise in the use of single-molecule, real-time (SMRT) sequencing technology for direct detection of DNA changes to develop a new assay for detecting mtDNA damage with a high resolution.
Impact on Diagnosis/Treatment of Parkinson's disease:
The improved resolution will allow the detection of mtDNA damage at unprecedented precision. This is expected to make a significant impact on both basic Parkinson's research and clinical practice. Our findings will facilitate disease diagnosis and aid in monitoring disease progression, designing clinical trials and analyzing their results, developing and testing new treatments. We also expect our findings to accelerate studies of the link between PD-associated genes and different forms of mtDNA damage.
Next Steps for Development:
Building on the progress made in assay development, we hope to use the assay to analyze biological samples from the LRRK2 Cohort Consortium, an initiative led by The Michael J. Fox Foundation to speed efforts to move LRRK2 toward therapeutic relevance for patients. We also plan to perform further analysis of mtDNA damage findings and other molecular and clinical data from the LRRK2 Cohort Consortium.