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Metabolomics and in-silico analysis reveal critical energy deregulations in animal models of Parkinson's disease

Pierre O. Poliquin, Jingkui Chen, Mathieu Cloutier, Louis-Éric Trudeau, Mario Jolicoeur

Article (2013)

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Abstract

Parkinson's disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a complex I blocker. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level.

Uncontrolled Keywords

Animals; Brain; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Computer Simulation; Disease Models, Animal; Energy Metabolism; Metabolomics; Mice; Mice, Knockout; Parkinson Disease; Stress, Physiological; Ubiquitin-Protein Ligases; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Ubiquitin-Protein Ligases; parkin protein

Subjects: 1800 Chemical engineering > 1800 Chemical engineering
6400 Life sciences research related to human health and disease > 6400 Life sciences research related to human health and disease
9000 Health sciences > 9000 Health sciences
Department: Department of Chemical Engineering
Research Center: GERAD - Research Group in Decision Analysis
Funders: CRSNG / NSERC - Discovery Grant, Canadian Foundation for Innovation, Canada Research Chair program, Canadian Institutes of Health Research, Brain Canada Foundation (Krembil Foundation)
PolyPublie URL: https://publications.polymtl.ca/3445/
Journal Title: PLOS One (vol. 8, no. 7)
Publisher: PLOS
DOI: 10.1371/journal.pone.0069146
Official URL: https://doi.org/10.1371/journal.pone.0069146
Date Deposited: 15 Jan 2019 13:40
Last Modified: 10 Nov 2022 14:40
Cite in APA 7: Poliquin, P. O., Chen, J., Cloutier, M., Trudeau, L.-É., & Jolicoeur, M. (2013). Metabolomics and in-silico analysis reveal critical energy deregulations in animal models of Parkinson's disease. PLOS One, 8(7). https://doi.org/10.1371/journal.pone.0069146

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