Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Abstract

Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes’ expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes.

Transcriptomic analyses suggest that mucopolysaccharidosis patients may be less susceptible to COVID‐19

“…PRJNA562649). The quality of the RNA‐seq data was confirmed previously and assessed to be reliable on the basis of RT‐qPCR analyses of selected genes [12–14]. Because of the severity of the disease, fibroblasts are most often used type of cells in genetic and genomic studies on MPS; in fact, availability of other biological material is technically and ethically poor, due to conditions of patients.…”

“…RNA isolation was conducted in four biological repeats for each cell line (i.e., four independent cultures from different passages). The procedure was performed exactly as described previously [12].…”

“…RNA-seq analyses were performed as described previously [12]. Raw data are deposited at NCBI Sequence Read Archive (SRA), under accession no.…”

Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses

“…Recent studies clearly indicated that secondary and tertiary changes (after the primary GAG storage) in cellular processes contribute significantly to the development of disorders and symptoms appearing in the course of MPS (Gaffke et al 2019;Fecarotta et al 2020). Significance of this aspect of MPS pathomechanism has been highlighted recently by discoveries of multiple changes in expression of genes coding for proteins involved in various cellular mechanisms in MPS (Brokowska et al 2020;Gaffke et al 2020;Pierzynowska et al 2020;Rintz et al 2020). Therefore, in this work, we have analyzed transcriptomic data, focusing on expression of genes coding for regulatory proteins responsible for the control of cellular processes.…”

Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism

“…Animal models and studies in humans demonstrated that impaired GAG degradation causes a deep alteration of cellular homeostasis involving pathways unrelated to the GAG metabolism [10,11,[13][14][15][16]. Indeed, defects in the lysosomal degradation of GAGs can be associated with dysfunctions in several biochemical and physiological processes such as the abnormal composition of membranes with an impact on vesicle fusion and trafficking, altered ganglioside and cholesterol metabolism, proteinase deregulation, impairment of autophagy and mitochondrial functions, and others [14][15][16][17][18][19][20]. Thus, a more detailed understanding of the pathogenetic events downstream of the altered GAG metabolism is still required.…”