Abstract
Introduction: Parkinson's disease (PD) is a neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons, accompanied by mitochondrial dysfunction. The contribution of mitochondrial DNA (mtDNA) variants to PD pathogenesis has long been debated. Nuclear genes driving inherited forms of PD, such as PRKN, are linked to mtDNA quality control mechanisms. Accordingly, a role of somatic mtDNA variants may play a role in mitochondrial dysfunction in PD. (reviewed in 1)
Materiel & Methods: mtDNA copy number and major arc deletion were analyzed in whole blood, lymphoblasts, fibroblasts, induced pluripotent stem cells (iPSCs) and iPSC-derived neurons of PD patients, healthy heterozygous PRKN variant carriers, and matched controls by digital droplet-PCR.
D-Loop activity was analyzed in the same samples by realtime-PCR. High coverage whole mtDNA genome sequences were obtained by next generation sequencing.
Results: An alteration of mtDNA copy number, D-Loop activity, and heteroplasmic variants was observed in iPSCs and -derived neurons as compared to blood cells. The correlation of heteroplasmy loads in iPSCs and neurons between controls and PRKN variant carriers was altered.
Conclusion: Advanced cellular models are indicated for the study of mitochondrial genotypes and its contribution to the cellular phenotype in PD. Deep mtDNA genotyping implies an altered mitochondrial quality control mechanism in PD-related mutation carriers.