Abstract
Homozygous or compound heterozygous variants in PRKN (Parkin) are causal for Parkinson´s disease (PD) with highly penetrant symptom expression, while the much more common heterozygous variants may predispose to PD in a dominant manner with highly reduced penetrance, through altered mitochondrial function. It is important to assess mitochondrial alteration in cells derived from PRKN heterozygous variant carriers, to establish potential molecular markers of presymptomatic mitochondrial dysfunction. In immortalized lymphocytes of non-manifesting heterozygous variant carriers, we measured a hyperactive mitochondrial respiration, and, although milder compared to a PRKN-linked PD patient, hiPSC-derived neurons of carriers also displayed several phenotypes of altered mitochondrial function. In blood samples, we also noticed a tendency towards increased mtDNA copy number. The identified phenotypes might be used to monitor heterozygous PRKN variant carriers during the prodromal phase, to recognize individuals at greater risk of eventual disease development and for testing potential mitochondrial-function-based neuroprotective therapies before neurodegeneration advances.