title: Parkin deficiency accelerates consequences of mitochondrial DNA deletions and Parkinsonism.
abstract: 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 19months; 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.
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States.
authors.forename: Lanying
authors.initials: L
authors.lastname: Song
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States.
authors.forename: Marissa
authors.initials: M
authors.lastname: McMackin
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States.
authors.forename: Andy
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States. Electronic address: gcortopassi@ucdavis.edu.
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Parkin deficiency; Parkinson's disease; Twinkle mutation; mtDNA deletion