Parkin deficiency accelerates consequences of mitochondrial DNA deletions and Parkinsonism

• Main Authors: Lanying Song, Marissa McMackin, Andy Nguyen, Gino Cortopassi
• Format: Article
• Language: English
• Published: Elsevier 2017-04-01
• Series: Neurobiology of Disease
• Subjects: Parkinson's disease; mtDNA deletion; Twinkle mutation; Parkin deficiency
• Online Access: http://www.sciencedirect.com/science/article/pii/S096999611630314X

Parkinson's disease (PD) is a neurodegenerative condition caused by age-related death of dopaminergic (DA) neurons in the substantia nigra (SN). Mitochondrial DNA (mtDNA) deletions rise exponentially with age in humans and reach their highest levels approaching 60% in dopaminergic neurons of the substantia nigra and overlap with dying neurons. Parkin deletion causes Parkinsonism in humans, presumably through a decrease in mitochondrial quality control, but Parkin knockout mice do not have DA neurodegeneration. We crossed Parkin knockouts to the Twinkle-TG mouse in which mtDNA deletions are increased specifically in substantia nigra to determine the effect of increased deletion mutagenesis in the absence of mitochondrial quality control. These double-mutant ‘TwinkPark’ mice had 1, the highest mtDNA deletion concentration in SN; 2, the lowest mitochondrial function and membrane potential; 3, the most severe neurobehavioral deficits at 19 months; 4, the least dopaminergic neurons in the SN and lowest dopamine levels, i.e. Parkinsonism. This mouse model could provide novel insights into the pathomechanism by which a specific increase in mtDNA deletions with age contribute to dopaminergic neurodegeneration and Parkinson's disease.