title: Neonatal mitochondrial abnormalities due to PINK1 deficiency: Proteomics reveals early changes relevant to Parkinson׳s disease.
abstract: Parkinson׳s disease (PD), the second most common neurodegenerative disorder, affects roughly 7-10 million people worldwide. A wide array of research has suggested that PD has a mitochondrial component and that mitochondrial dysfunction occurs well in advance of the clinical manifestation of the disease. Previous work by our lab has categorized the mitochondrial disorder associated with Parkinson׳s disease in a PINK1 knockout rat model. This model develops Parkinson׳s disease in a spontaneous, predictable manner. Our findings demonstrated PINK1-deficient rats at 4 months of age had mitochondrial proteomic and functional abnormalities before the onset of Parkinsonian symptoms (6 months) such as the movement disorder, loss of midbrain dopaminergic neurons, or the progressive degeneration present at 9 months. With this in mind, our group investigated the PINK1 knockout genetic rat model at postnatal day 10 to determine if the observed alterations at 4 months were present at an earlier time point. Using a proteomic analysis of brain mitochondria, we identified significant mitochondrial proteomic alterations in the absence of mitochondrial functional changes suggesting the observed alterations are part of the mitochondrial pathways leading to PD. Specifically, we identified differentially expressed proteins in the PINK1 knockout rat involved in glycolysis, the tricarboxylic acid cycle, and fatty acid metabolism demonstrating abnormalities occur well in advance of the manifestation of clinical symptoms. Additionally, 13 of the differentially expressed proteins have been previously identified in older PINK1 knockout animals as differentially regulated suggesting these proteins may be viable markers of the PD pathology, and further, the abnormally regulated pathways could be targeted for therapeutic interventions. All raw data can be found in Supplementary Table 1.
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors: Lance M
authors: LM
authors: Villeneuve
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors: Phillip R
authors: PR
authors: Purnell
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors: Kelly L
authors: KL
authors: Stauch
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors: Howard S
authors: HS
authors: Fox