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Neurobiol Dis. 2017 Apr;100:30-38. doi: 10.1016/j.nbd.2016.12.024. Epub 2016 Dec 29.

Parkin deficiency accelerates consequences of mitochondrial DNA deletions and Parkinsonism.

Author information

1
Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States.
2
Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States. Electronic address: gcortopassi@ucdavis.edu.

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.

KEYWORDS:

Parkin deficiency; Parkinson's disease; Twinkle mutation; mtDNA deletion

PMID:
28042097
DOI:
10.1016/j.nbd.2016.12.024
[Indexed for MEDLINE]

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