Abstract
Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSD) caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans (GAGs). Most types of these severe disorders are characterized by neuronopathic phenotypes. Although lysosomal accumulation of GAGs is the primary metabolic defect in MPS, secondary alterations in biochemical processes are considerable and influence the course of the disease. Early hypothesis suggested that these secondary changes might be due to lysosomal storage-mediated impairment of activities of other enzymes, and subsequent accumulation of various compounds in cells. However, recent studies indicated that expression of hundreds of genes is changed in MPS cells. Therefore, we asked whether metabolic effects observed in MPS are caused primarily by GAG-mediated inhibition of specific biochemical reactions or appear as results of dysregulation of expression of genes coding for proteins involved in metabolic processes. Transcriptomic analyses of 11 types of MPS (using RNA isolated from patient-derived fibroblasts), performed in this study, showed that a battery of the above mentioned genes is dysregulated in MPS cells. Some biochemical pathways might be especially affected by changes in expression of many genes, including GAG metabolism and sphingolipid metabolism which is especially interesting as secondary accumulation of various sphingolipids is one of the best known additional (while significantly enhancing neuropathological effects) metabolic defects in MPS. We conclude that severe metabolic disturbances, observed in MPS cells, can partially arise from changes in the expression of many genes coding for proteins involved in metabolic processes.