Understanding the Metabolic Consequences of Human Arylsulfatase A Deficiency through a Computational Systems Biology...

The nervous system is responsible for the communication between the organism and its environment. This task is possible by the presence of the myelin sheath, which is a double membrane formed by about 75% lipids and 25% proteins. The sulfatide represents one of the main lipids of the myelin band; its degradation is catabolized by the enzyme Arylsulfatase A (ARSA), to generated galactosylceramide. Mutations affecting ARSA function lead to the neurodegenerative disease Metachromatic Leukodystrophy. This disease is characterized by accumulation of sulfatide within the band of myelin affecting its functionality. The biochemical consequences of ARSA deficiency are not well understood yet. In this paper, we used an in-silico systems-biology approach to model the biochemical consequences of ARSA deficiency within a general human metabolic network (Recon2) and a glia cellular model. We expected that ARSA deficiency mainly affected the glycosphingolipid pathways. However, the results suggest that mitochondrial metabolism and amino acid transport were the main reactions affected within both cellular models. In the glia cell model, it was highlighted the high number of affected reactions of neurotransmitters metabolism, while only a reduced effect was observed in reactions involved in glycosphingolipids metabolism. We hypothesize that ARSA deficiency might lead to metabolic consequences that not only compromise the myelin band or the glycosphingolipids metabolism but also the overall metabolic function of the nervous system. Furthermore, these results offer the bases for the design of in-vitro and in-vivo experiments that allow generating new knowledge of MLD pathophysiology and other neurodegenerative diseases.