Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses.

Joanna Brokowska,Lidia Gaffke,Karolina Pierzynowska,Estera Rintz,Grzegorz Węgrzyn,Magdalena Podlacha,Zuzanna Cyske

doi:10.3390/ijms21093194

Joanna Brokowska, Lidia Gaffke + Show 5 more

Open Access

https://doi.org/10.3390/ijms21093194

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Abstract

Although mucopolysaccharidoses (MPS), inherited metabolic diseases from the group of lysosomal storage diseases (LSD), are monogenic disorders, recent studies indicated that their molecular mechanisms are complicated. Storage of glycosaminoglycans (GAGs), arising from a deficiency in one of the enzymes involved in the degradation of these compounds, is the primary cause of each MPS type. However, dysfunctions of various cellular organelles and disturbance of cellular processes have been reported which contribute considerably to pathomechanisms of the disease. Here, we present a complex transcriptomic analysis in which all types and subtypes of MPS were investigated, with special emphasis on genes related to cell activation processes. Complex changes in expression of these genes were found in fibroblasts of all MPS types, with number of transcripts revealing higher or lower levels (relative to control fibroblasts) between 19 and over 50, depending on MPS type. Genes in which expression was significantly affected in most MPS types code for proteins involved in following processes, classified according to Gene Ontology knowledge database: cell activation, cell growth, cell recognition, and cell division. Levels of some transcripts (including CD9, CLU, MME and others) were especially significantly changed (over five times relative to controls). Our results are discussed in the light of molecular pathomechanisms of MPS, indicating that secondary and/or tertiary changes, relative to GAG storage, might significantly modulate cellular dysfunctions and contribute to molecular mechanisms of the disease. This may influence the efficacy of various therapies and suggests why various treatments are not fully effective in improving the complex symptoms of MPS.

Highlights

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases occurring with a frequency of 1 in 40,000–50,000 live births [1]
As the disturbances of processes of cell activation, growth, division and differentiation have not been studied previously at the molecular level in the context of MPS pathogenesis, transcriptomic analyses of these processes in fibroblasts derived from patients with all types of MPS, and healthy control (HDFa line) cells (Table 2), were performed
The results indicated that the number of transcripts whose levels were significantly different (FDR < 0.1; p < 0.1) in MPS cells relative to healthy cells is most noticeable in the case of cell activation (GO: 0001775) process and ranges from 19 to as much as over 50

Summary

Introduction

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases occurring with a frequency of 1 in 40,000–50,000 live births [1]. They are caused by the lack or residual activity of glycosaminoglycan (GAG)-degrading enzymes, causing an accumulation of these polysaccharides in lysosomes, impairing cell functions. Symptoms of the disease usually appear between two and four years of age (depending on the type) and include organomegaly (mainly liver and spleen enlargement), thickening of the skin and subcutaneous tissue, which results in coarse facial features, as well as deformations within the skeleton, leading to disability of movement [1]. The severity of the symptoms depend on many factors, among which the total lack or residual activity of lysosomal enzymes, the effectiveness of GAG synthesis [2] as well as environmental factors [3] or access to rehabilitation [4] and emergency assistance [5] can be mentioned

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