title: Systematic analysis of transcription-level effects of neurodegenerative diseases on human brain metabolism by a newly reconstructed brain-specific metabolic network.
abstract: Network-oriented analysis is essential to identify those parts of a cell affected by a given perturbation. The effect of neurodegenerative perturbations in the form of diseases of brain metabolism was investigated by using a newly reconstructed brain-specific metabolic network. The developed stoichiometric model correctly represents healthy brain metabolism, and includes 630 metabolic reactions in and between astrocytes and neurons, which are controlled by 570 genes. The integration of transcriptome data of six neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia) with the model was performed to identify reporter features specific and common for these diseases, which revealed metabolites and pathways around which the most significant changes occur. The identified metabolites are potential biomarkers for the pathology of the related diseases. Our model indicated perturbations in oxidative stress, energy metabolism including TCA cycle and lipid metabolism as well as several amino acid related pathways, in agreement with the role of these pathways in the studied diseases. The computational prediction of transcription factors that commonly regulate the reporter metabolites was achieved through binding-site analysis. Literature support for the identified transcription factors such as USF1, SP1 and those from FOX families are known from the literature to have regulatory roles in the identified reporter metabolic pathways as well as in the neurodegenerative diseases. In essence, the reconstructed brain model enables the elucidation of effects of a perturbation on brain metabolism and the illumination of possible machineries in which a specific metabolite or pathway acts as a regulatory spot for cellular reorganization.
authors: Department of Bioengineering, Gebze Institute of Technology, Gebze, Kocaeli, Turkey ; Department of Chemical Engineering, Boğaziçi University, 34342 Bebek, Istanbul, Turkey.
authors: Mustafa
authors: M
authors: Sertbaş
authors: Department of Chemical Engineering, Boğaziçi University, 34342 Bebek, Istanbul, Turkey.
authors: Kutlu
authors: K
authors: Ulgen
authors: Department of Bioengineering, Gebze Institute of Technology, Gebze, Kocaeli, Turkey.
authors: Tunahan
authors: T
authors: Cakır
keywords: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; Brain metabolic network; Computational systems biology; FBA, flux balance analysis; GABA, gamma-aminobutyric acid; HD, Huntington’s disease; KIV, ketoisovalerate; KLF, Krüppel-like factor; KMV, alpha-keto-beta-methylvalerate; MS, multiple sclerosis; Neurodegenerative diseases; Neurometabolism; PCA, principal component analysis; PD, Parkinson’s disease; RMA, reporter metabolite analysis; RPA, reporter pathway analysis; Reporter metabolite; SCHZ, schizophrenia; TCA, tricarboxylic acid; Transcriptome; USF, upstream stimulatory factor