Lack of parkin anticipates the phenotype and affects mitochondrial morphology and mtDNA levels in a mouse model of parkinson’s disease

Milena Pinto, Nadee Nissanka, Carlos T Moraes

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

PARK2 is the most common gene mutated in monogenic recessive familial cases of Parkinson’s disease (PD). Pathogenic mutations cause a loss of function of the encoded protein Parkin. ParkinKO mice, however, poorly represent human PD symptoms as they only exhibit mild motor phenotypes, minor dopamine metabolism abnormalities, and no signs of dopaminergic neurodegeneration. Parkin has been shown to participate in mitochondrial turnover, by targeting damaged mitochondria with low membrane potential to mitophagy. We studied the role of Parkin on mitochondrial quality control in vivo by knocking out Parkin in the PD-mito-PstI mouse (males), where the mitochondrial DNA (mtDNA) undergoes double-strand breaks only in dopaminergic neurons. The lack of Parkin promoted earlier onset of dopaminergic neurodegeneration and motor defects in the PD-mito-PstI mice, but it did not worsen the pathology. The lack of Parkin affected mitochondrial morphology in dopaminergic axons and was associated with an increase in mtDNA levels (mutant and wild type). Unexpectedly, it did not cause a parallel increase in mitochondrial mass or mitophagy. Our results suggest that Parkin affects mtDNA levels in a mitophagy-independent manner.

Original languageEnglish (US)
Pages (from-to)1042-1053
Number of pages12
JournalJournal of Neuroscience
Volume38
Issue number4
DOIs
StatePublished - Jan 24 2018

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Mitochondrial Degradation
Mitochondrial DNA
Parkinson Disease
Phenotype
Mitochondrial Turnover
Dopaminergic Neurons
Quality Control
Membrane Potentials
Axons
Dopamine
Mitochondria
Pathology
Mutation
Genes

Keywords

  • Deletion
  • Double-strand breaks
  • Mitochondria
  • Mitophagy
  • MtDNA
  • Parkinson

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Lack of parkin anticipates the phenotype and affects mitochondrial morphology and mtDNA levels in a mouse model of parkinson’s disease. / Pinto, Milena; Nissanka, Nadee; Moraes, Carlos T.

In: Journal of Neuroscience, Vol. 38, No. 4, 24.01.2018, p. 1042-1053.

Research output: Contribution to journalArticle

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