The effect of molecular crowding on Parkinson's disease by using a genome-scale metabolic network.

Objective: In this study, genome-scale transcriptome data derived from Parkinson's disease patients are analyzed using bioinformatics methods to estimate significantly changed cellular pathways. Methods: A brain-specific genome-scale metabolic network model previously developed by our group, called iMS570, is used in the analysis. It is the most comprehensive metabolic network model in the literature. Here, we improved iMS570 by fully compartmenting all the reactions as cytosolic or mitochondrial based on the location of the catalyzing enzymes. The updated network included 799 reactions, a considerable improvement compared to the original model that included 630 reactions. The new metabolic network is called iBrain799. Since the aggregation of the alpha-synuclein protein in Parkinson's disease is a well-known phenomenon, the effect of molecular crowding on the functioning of metabolism was investigated in this study using iBrain799 and disease-specific transcriptome data. A computational approach which allows the prediction of reaction rates, called Flux Balance Analysis, was used for this purpose. Results: As a result of simulations, it was observed that the activity of energy metabolism decreased as the molecular crowding due to protein accumulation increased. Conclusion: The results reveal the effect of molecular crowding on Parkinson's disease as a function of the increase in the level of alpha-synuclein. This result is reasonable because if molecular crowding increases, then it becomes difficult for the enzyme to reach the substrates. For this reason, the rate of metabolism decreases. Low metabolism is a common phenomenon in neurodegenerative diseases, as in Parkinson's disease. When considered from this point of view, the use of the molecular crowding constraint in simulations gives realistic results. This research was financially supported by TUBITAK (Grant Number: 315S302) and TÜBA-GEBİP (2015). [ABSTRACT FROM AUTHOR]