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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 and Mario Jolicoeur

Article (2013)

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Cite this document: 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). doi:10.1371/journal.pone.0069146
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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

Open Access document in PolyPublie
Subjects: 1800 Génie chimique > 1800 Génie chimique
6400 Recherche en sciences de la vie liées la santé publique et aux maladies humaines > 6400 Recherche en sciences de la vie liées la santé publique et aux maladies humaines
9000 Sciences médicales > 9000 Sciences médicales
Department: Département de génie chimique
Research Center: GERAD - Groupe d'études et de recherche en analyse des décisions
Funders: CRSNG / NSERC - Discovery Grant, Canadian Foundation for Innovation, Canada Research Chair program, Canadian Institutes of Health Research, Brain Canada Foundation (Krembil Foundation)
Date Deposited: 15 Jan 2019 13:40
Last Modified: 16 Jan 2019 01:20
PolyPublie URL: https://publications.polymtl.ca/3445/
Document issued by the official publisher
Journal Title: PloS One (vol. 8, no. 7)
Publisher: PLOS
Official URL: https://doi.org/10.1371/journal.pone.0069146

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