Parkin deficiency accelerates consequences of mitochondrial DNA deletions and Parkinsonism

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


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.

MeSH terms

  • Animals
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Mice, Transgenic
  • Mitochondria / genetics*
  • Mutation / genetics
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism
  • Substantia Nigra / metabolism
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / metabolism*


  • DNA, Mitochondrial
  • Ubiquitin-Protein Ligases
  • parkin protein