Early Expression of Parkinson’s Disease-Related Mitochondrial Abnormalities in PINK1 Knockout Rats

Lance M. Villeneuve, Phillip R. Purnell, Michael D. Boska, Howard S. Fox

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

PTEN-induced kinase 1 (PINK1) mutations are responsible for an autosomal recessive, familial form of Parkinson’s disease. PINK1 protein is a Ser/Thr kinase localized to the mitochondrial membrane and is involved in many processes including mitochondrial trafficking, mitophagy, and proteasomal function. Using a new PINK1 knockout (PINK1 KO) rat model, we found altered brain metabolomic markers using magnetic resonance spectroscopy, identified changes in mitochondrial pathways with quantitative proteomics using sequential window acquisition of all theoretical spectra (SWATH) mass spectrometry, and demonstrated mitochondrial functional alterations through measurement of oxygen consumption and acidification rates. The observed alterations included reduced creatine, decreased levels of complex I of the electron transport chain, and increased proton leak in the electron transport chain in PINK1 KO rat brains. In conjunction, these results demonstrate metabolomic and mitochondrial alterations occur during the asymptomatic phase of Parkinson’s disease in this model. These results indicate both potential early diagnostic markers and therapeutic pathways that can be used in PD.

Original languageEnglish (US)
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Nov 25 2014

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Phosphotransferases
Metabolomics
Mitochondrial Degradation
Electron Transport Complex I
Creatine
Brain
Mitochondrial Membranes
Parkinsonian Disorders
Electron Transport
Oxygen Consumption
Proteomics
Protein Kinases
Parkinson Disease
Protons
Mass Spectrometry
Magnetic Resonance Spectroscopy
Mutation
Mitochondrial Parkinson Disease
Therapeutics

Keywords

  • Mitochondria
  • Neurodegeneration
  • Parkinson’s disease
  • Proton leak

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Early Expression of Parkinson’s Disease-Related Mitochondrial Abnormalities in PINK1 Knockout Rats. / Villeneuve, Lance M.; Purnell, Phillip R.; Boska, Michael D.; Fox, Howard S.

In: Molecular Neurobiology, 25.11.2014.

Research output: Contribution to journalArticle

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