Objective: The overall objective of this project is to gain essential knowledge on the contribution of genetic variability in nuclear-encoded mitochondrial proteins to idiopathic Parkinson’s disease (iPD) pathogenesis. Starting from genomic data, we aim to functionally validate mitochondrial polygenic risk profiles in patient-based cellular models, thus defining mitochondrial pathways potentially involved in neurodegeneration in subgroups of iPD patients.

Background: A large body of evidence specifically points to mitochondrial dysfunction as major cause of PD pathogenesis. Given that only ~10% of PD cases can be attributed to monogenic causes, we hypothesize that a fraction of iPD cases may harbour a pathogenic combination of common variants in mitochondrial genes ultimately resulting in mitochondrial dysfunction.

Method: To decipher this mitochondria-related “missing heritability”, we used GWAS common SNPs (MAF ≥ 1%) data from the Luxembourg Parkinson’s study (412 iPD patients and 576 healthy controls), and calculated mitochondria-specific polygenic risk scores (mitoPRS) to capture the cumulative effect of common variants in mitochondrial genes on PD risk. Skin fibroblasts and iPSC-derived neuronal progenitor cells from iPD patients were identified based on their mitoPRS and then subjected to a comprehensive mitochondrial phenotyping.

Results: We found that distribution of mitoPRS was significantly associated with PD in the Luxembourg Parkinson’s study. Extending the PRS approach to selected mitochondrial pathways, we demonstrated that common variants in genes regulating three distinct mitochondrial pathways were associated with a higher PD risk. Functional characterization of skin fibroblasts and corresponding iPSC-derived neuronal progenitor cells from iPD patients classified based on these mitochondria-specific PRSs revealed significant differences in certain mitochondrial phenotypic readouts between the high- and low-PRS groups.

Conclusion: We developed and functionally validated novel mitochondria-specific PRSs that could be used as a genetic tool to stratify the heterogeneous group of iPD patients. Using patient-based models relying on these mitochondrial signatures for drug screening approaches may pave the way for future more tailored therapeutic strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/functional-validation-of-a-mitochondria-specific-polygenic-risk-score-in-patient-based-models-for-stratification-of-idiopathic-parkinsons-disease/