Study Rationale: In the majority of people with Parkinson's disease (PWP), the movement disorder is not caused by mutations in a single gene. Until recently, these people were considered “sporadic” cases. However, novel research suggests that common non-disease-causing variants in genes that function in the same cellular pathways, particularly those related to mitochondria (the powerhouses of the cell), may increase the risk of developing PD. The cumulative effect of such variants can be determined by calculating so-called “polygenic risk scores”, or “PRSs” for short. To test the functional relevance of different mitochondrial PRSs (mito-PRSs), we generated cellular models from individuals of our local PD cohort with low or high scores and found that in the latter cultures mitochondrial homeostasis was indeed impaired.
Hypothesis: We hypothesize that PWP with high mito-PRSs will show distinct changes at the cellular level that may also influence their response to mitochondrial-targeted therapies.
Study Design: We will extend our previous work by studying the rich omics data-sets available from the PPMI cohort. We will investigate how different mito-PRSs affect gene activity and expression. In addition, we will test whether high mito-PRSs affect the integrity of the mitochondrial genome. Next, we will explore whether combining mito-PRS with mitochondrial genomic data can discriminate better PWP from controls than either genetic data-set alone. Finally, we will validate key findings from the PPMI cohort in samples from our Luxembourgish PD cohort.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this study could lead to more accurate methods for diagnosing PWP and identifying, which patients might benefit most from specific treatments targeting mitochondria
Next Steps for Development: If our findings are confirmed, the next steps would involve developing mito-PRSs into tools that could be used in clinical trials to better select patients for mitochondrial-targeted therapies.