Identifying Parkinson’s disease penetrance-modifying factors in the population-based Cooperative Health Research in South Tyrol (CHRIS) cohort

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The largest described pedigree of Parkin mutation carriers (n=77) originates from South Tyrol and includes numerous heterozygous carriers of Parkin mutation carriers who develop overt symptoms of Parkinson’s disease (PD), while others may have prodromal, or no obvious symptoms. We aim to dissect out the factors that modify the penetrance of these variants, using additional mutation carriers in the Cooperative Health Research in South Tyrol (CHRIS) study (n=13,490 from the same geographical region). In the first funding period, testing whether factors that influence mitochondrial function can alter penetrance of nuclear mutations causing mitochondrial dysfunction, we observed an increased burden of mtDNA mutations in affected vs. unaffected heterozygous Parkin and PINK1 (Phosphatase and tensin homolog-induced putative kinase 1) mutation carriers and compared to non-carriers, which might explain the phenotypic (clinical, sub-clinical) discordance in these individuals with similar nuclear genetic background. However, the specificity of mtDNA variation as a penetrance marker and the molecular pathways of increased mtDNA mutation load ultimately leading to neurodegeneration, require further investigation with larger datasets. We hypothesize that there will be a penetrance-modifying interaction between mutations in PD genes and mitochondrial function, influenced by both mtDNA mutation burden and/or copy number, through mechanisms that involve mtDNA maintenance. In Objective 1, we will identify additional Parkin mutation carriers (expected total n=650) in the CHRIS study and characterize them phenotypically for signs and symptoms of prodromal or overt PD. From a successful recall-by-genotype pilot study, we have established the ethics framework to recall carriers for deeper phenotyping and identified phenotypes that appear able to distinguish carriers and non-carriers in the pilot study. Using deep mitochondrial sequencing, in Objective 2, we will determine the mtDNA mutational load and damaging mtDNA variants in blood from carriers of pathogenic Parkin variants identified in Objective 1. We will test whether these variables influence disease penetrance/expressivity, and specifically look whether it is possible to detect a threshold of mutation burden that predicts sub-clinical or clinical phenotype appearance. In Objective 3, we will test the causal link between pathogenic variants in Parkin, mtDNA mutations and expressivity of molecular phenotypes of mitochondrial function in neuronal cell models, and test mechanisms that might rescue mitochondrial function in the presence of such Parkin and mtDNA variants. We will characterize biosamples drawn from participants at different time points to see changes over time. This might allow interventional studies to test neuroprotective strategies (genetic or pharmacological) aimed at normalizing mitochondrial function in the presence of Parkin mutations, or in other genes that influence mitochondrial function.