Metabolomics and in-silico analysis reveal critical energy deregulations in animal models of Parkinson's disease.
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 mitochondrial uncoupler [corrected]. 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.
Department of Chemical Engineering, École Polytechnique de Montréal, Montréal, Quebec, Canada.
Pierre O
PO
Poliquin
Jingkui
J
Chen
Mathieu
M
Cloutier
Louis-Éric
LÉ
Trudeau
Mario
M
Jolicoeur
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000633:toxicity; D003198:Computer Simulation; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics
D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein