title: Early Expression of Parkinson's Disease-Related Mitochondrial Abnormalities in PINK1 Knockout Rats.
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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors.forename: Lance M
authors.initials: LM
authors.lastname: Villeneuve
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Purnell
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.|Department of Radiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boska
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA. hfox@unmc.edu.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Fox
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D051381:Rats; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase
keywords: Mitochondria; Neurodegeneration; Parkinson’s disease; Proton leak