Objective: Here, we aim to identify functional interactions between the Parkinson’s disease-associated genes.

Background: Understanding how genes interact to produce a given phenotype is a challenge of immense significance. Mitochondrial defects are cellular hallmarks in familial Parkinson’s disease (PD) and idiopathic forms with unknown etiology.

Method: We systematically map functional interactions between PD-related genes. High-Content Screening in differentiated SH-SY5Y cells combines pairwise combinatorial perturbations with custom algorithms to analyze mitophagy, non-quenching TMRM assays, and lethality. We developed custom baculoviral vectors for pairwise perturbations and predicted functional gene-gene interactions via deviation from the expectation models.

Results: The key result is a functional interaction map between PD-associated genes that integrates cellular lethality, mitochondrial membrane potential, and mitophagy.

Conclusion: Many of the observed genetic interactions need to be confirmed by mechanistic studies, and the clinical relevance needs to be confirmed in patient-derived cellular models. We are convinced that the present work leverages the stratification of PD-subtypes based on functional mitochondrial profiling.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/systematic-mapping-of-parkinsons-disease-gene-interactions/