Use of a neuron-glia genome-scale metabolic reconstruction to model the metabolic consequences of the Arylsulphatase a deficiency through a systems biology approach
Olga Y. Echeverri-Peña,
Diego A. Salazar-Barreto,
Alexander Rodríguez-Lopez,
Janneth González,
Carlos J. Alméciga-Díaz,
Cristian H. Verano-Guevara,
Luis A. Barrera
Affiliations
Olga Y. Echeverri-Peña
Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Corresponding author.
Diego A. Salazar-Barreto
Centro para la Optimización y Probabilidad Aplicada (COPA), Department of Industrial Engineering, Faculty of Engineering, Universidad de los Andes, Bogotá D.C., Colombia; Grupo de Bioquímica Computacional, Estructural y Bioinformática, Department of Nutrition and Biochemistry, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia
Alexander Rodríguez-Lopez
Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Licenciatura en Química, Universidad Distrital Francisco Jose de Caldas, Bogota D.C., Colombia; Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá D.C., Colombia
Janneth González
Grupo de Bioquímica Computacional, Estructural y Bioinformática, Department of Nutrition and Biochemistry, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia
Carlos J. Alméciga-Díaz
Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Corresponding author.
Cristian H. Verano-Guevara
Licenciatura en Química, Universidad Distrital Francisco Jose de Caldas, Bogota D.C., Colombia
Luis A. Barrera
Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Clínica de Errores Innatos del Metabolismo, Hospital Universitario San Ignacio, Bogotá D.C., Colombia
Metachromatic leukodystrophy (MLD) is a human neurodegenerative disorder characterized by progressive damage on the myelin band in the nervous system. MLD is caused by the impaired function of the lysosomal enzyme Arylsulphatase A (ARSA). The physiopathology mechanisms and the biochemical consequences in the brain of ARSA deficiency are not entirely understood. In recent years, the use of genome-scale metabolic (GEM) models has been explored as a tool for the study of the biochemical alterations in MLD. Previously, we modeled the metabolic consequences of different lysosomal storage diseases using single GEMs. In the case of MLD, using a glia GEM, we previously predicted that the metabolism of glycosphingolipids and neurotransmitters was altered. The results also suggested that mitochondrial metabolism and amino acid transport were the main reactions affected. In this study, we extended the modeling of the metabolic consequences of ARSA deficiency through the integration of neuron and glial cell metabolic models. Cell-specific models were generated from Recon2, and these were used to create a neuron-glial bi-cellular model. We propose a workflow for the integration of this type of model and its subsequent study. The results predicted the impairment pathways involved in the transport of amino acids, lipids metabolism, and catabolism of purines and pyrimidines. The use of this neuron-glial GEM metabolic reconstruction allowed to improve the prediction capacity of the metabolic consequences of ARSA deficiency, which might pave the way for the modeling of the biochemical alterations of other inborn errors of metabolism with central nervous system involvement.
