Objective/Rationale:
Over the last decade genetic causes of Parkinson’s disease have given great insights into the pathways and mechanisms that play a role in the disease. The discovery of common genetic mutations that result in both familial and sporadic disease forms have shown that these two entities are not distinct. These genes and the protein products have also been the driving force behind disease-model systems and the directed the therapeutic intervention strategies that are being promoted.
Project Description:
Genetic variation of the LRRK2 gene has been shown to play an important role in both familial and sporadic Parkinson’s disease. Although over one hundred variations in the protein coding sequence of the LRRK2 gene have been identified only seven have been proven as pathogenic. This project has set out to evaluate the pathogenic nature of every LRRK2 coding variant, and in addition generate estimates of prevalence and penetrance for each defined pathogenic variant. We will also assess the possible role of multiple LRRK2 variants acting together to result in disease manifestation. This project will examine over ten thousand samples for the library of LRRK2 variations from different populations to address these critical questions.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Individualized medicine will rely on genetic characterization of each variant to determine its impact on disease risk and diagnostic outcome. Resolving the full impact of LRRK2 variation on Parkinson’s disease including the frequency, penetrance and pathogenicity of coding variations will identify those individuals whose disease risk is modulated by LRRK2. As therapeutics are identified which are targeted to the Lrrk2 protein it will be important for clinical trials of efficacy and effectiveness that the study subjects are selected based on those most likely to benefit.
Anticipated Outcome:
This study will identify and confirm pathogenicity for a number of LRRK2 variations. It will reveal the general influence LRRK2 variation has on Parkinson’s disease across the globe. We anticipate our study will act as reference to clinicians who exploit LRRK2 genetic testing as part of their diagnostic arsenal. This study will also add further insight in the pathogenic mechanisms underlying LRRK2-parkinsonism and will direct and advance the on-going development of Parkinson’s disease therapeutics.