PROTECTMOVE

Genes causative for recessively inherited Parkinson’s disease (PD) include Parkin (PRKN) and PINK1; rare homozygous mutations in these genes result in definite symptom expression. On the other hand, evidence suggests that heterozygous mutations – a relatively common occurrence – may predispose to PD in a dominant manner with highly reduced penetrance. The largest described pedigree of PRKN mutation carriers (n=77) originates from South Tyrol and includes numerous heterozygous carriers of PRKN mutations who develop overt symptoms of Parkinson’s disease (PD), while others may have prodromal, or no obvious symptoms. In this project, we aim to dissect out the factors that modify the penetrance of these variants, using additional PRKN mutation carriers identified in the Cooperative Health Research in South Tyrol (CHRIS) study (comprising n=13,490 individuals from the same geographical region). By testing whether factors that influence mitochondrial function can alter penetrance of nuclear mutations, we observed an increased burden of heteroplasmic mtDNA mutations in affected vs. unaffected heterozygous PRKN and PINK1 mutation carriers, which might explain the phenotypic (clinical, sub-clinical) discordance in these individuals with similar nuclear genetic background. In addition, induced pluripotent stem cell (iPSC)-derived neurons of non-PD manifesting heterozygous mutation carriers displayed several phenotypes of altered mitochondrial function. This project was part of the DFG (Deutsche Forschungsgemeinschaft) funded research group ProtectMove (FOR2488).