Actin Cytoskeleton Polymerization and Focal Adhesion as Important Factors in the Pathomechanism and Potential Targets of Mucopolysaccharidosis Treatment

Abstract

The main approach used in the current therapy of mucopolysaccharidosis (MPS) is to reduce the levels of glycosaminoglycans (GAGs) in cells, the deposits considered to be the main cause of the disease. Previous studies have revealed significant differences in the expression of genes encoding proteins involved in many processes, like those related to actin filaments, in MPS cells. Since the regulation of actin filaments is essential for the intracellular transport of specific molecules, the process which may affect the course of MPSs, the aim of this study was to evaluate the changes that occur in the actin cytoskeleton and focal adhesion in cells derived from patients with this disease, as well as in the MPS I mouse model, and to assess whether they could be potential therapeutic targets for different MPS types. Western-blotting, flow cytometry and transcriptomic analyses were employed to address these issues. The levels of the key proteins involved in the studied processes, before and after specific treatment, were assessed. We have also analyzed transcripts whose levels were significantly altered in MPS cells. We identified genes whose expressions were changed in the majority of MPS types and those with particularly highly altered expression. For the first time, significant changes in the expression of genes involved in the actin cytoskeleton structure/functions were revealed which may be considered as an additional element in the pathogenesis of MPSs. Our results suggest the possibility of using the actin cytoskeleton as a potential target in therapeutic approaches for this disease.

Co-Analysis of Serum and Urine Differentially Expressed Proteins in Mucopolysaccharidosis Type I

“…We next performed function enrichment analysis on these DEPs (Figure C,D) and found that a majority of them are associated with controlling the transport of molecules inside and outside the cell, signaling pathways, and regulation of cellular morphology. Based on the current reports on the pathogenesis of MPS I − and the accuracy and credibility of the obtained enrichment data, 20 relevant proteins (Table S2) were selected from cellular components involved in endocytic vesicle, growth factor binding, and vesicle lumen for PRM verification. Serum samples from another 6 MPS I and 6 healthy controls were collected for PRM experiments.…”

“…9 The study found that the diagnosis time of MPS I in various regions is generally delayed. 10 It is necessary to facilitate the detection of biochemical markers, but the complex pathogenesis limits the application of the commonly used urine glycosaminoglycan assay. 11 Most studies have simply focused on biomarkers of certain body fluids or other kinds of biospecimens in MPS I patients, which may result in a large research bias for the reason that MPS I is rare and the number of included patients is usually not enough.…”

“…However, while the early symptoms of MPS I are nonspecific, such as airway obstruction, hernia, etc., early diagnosis is usually hindered . The study found that the diagnosis time of MPS I in various regions is generally delayed . It is necessary to facilitate the detection of biochemical markers, but the complex pathogenesis limits the application of the commonly used urine glycosaminoglycan assay .…”

Enhanced Efficiency of the Basal and Induced Apoptosis Process in Mucopolysaccharidosis IVA and IVB Human Fibroblasts

“…Importantly, apart from secondary biochemical changes and dysmorphology in cellular organelles [ 13 , 14 ], crucial processes occurring in MPS cells were demonstrated to be significantly affected [ 15 ]. They include proteasome activity [ 16 ], ion homeostasis [ 17 ], signal transduction [ 18 ], cell cycle [ 19 ], vesicle trafficking [ 20 ], actin cytoskeleton polymerization [ 21 ], and apoptosis [ 22 ]. Dysregulation of the last of the mentioned processes has been demonstrated mostly by finding changes in the expression of the genes involved, directly or indirectly, in apoptosis [ 22 ].…”

“…In this study, we used fibroblasts derived from MPS IVA and IVB patients as cellular models of the diseases. Such cells were previously employed during MPS investigations, indicating that experiments with fibroblasts can give reliable results in studies on molecular mechanisms of MPS [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”