Changes in cellular processes occurring in mucopolysaccharidoses as underestimated pathomechanisms of these diseases

Abstract

Mucopolysaccharidoses (MPS) are a group of genetic disorders belonging to lysosomal storage diseases. They are caused by genetic defects leading to a lack or severe deficiency of activity of one of lysosomal hydrolases involved in degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate in lysosomes, which results in dysfunctions of cells, tissues, and organs. Until recently, it was assumed that GAG accumulation in cells is the major, if not the only, mechanism of pathogenesis in MPS, as GAGs may be a physical ballast for lysosomes causing inefficiency of cells due to a large amount of a stored material. However, recent reports suggest that in MPS cells there are changes in many different processes, which might be even more important for pathogenesis than lysosomal accumulation of GAGs per se. Moreover, there are many recently published results indicating that lysosomes not only are responsible for degradation of various macromolecules, but also play crucial roles in the regulation of cellular metabolism. Therefore, it appears plausible that previous failures in treatment of MPS (i.e., possibility to correct only some symptoms and slowing down of the disease rather than fully effective management of MPS) might be caused by underestimation of changes in cellular processes and concentration solely on decreasing GAG levels in cells.

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

“…In fact, frequent and severe respiratory tract infections were reported as being among characteristic symptoms of enzyme replacement therapy interruption in MPS patients [29–31]. Nevertheless, presented analyses may shed a new light on the MPS course, underlining the importance of modifications of cellular processes, arising from changes in gene expression regulations, in the pathomechanism (as proposed recently [32]), and suggesting that patients suffering from this disease might reveal certain features making them potentially less susceptible to some other diseases.…”

“…As indicated in recently published reports [12–14], expression of hundreds of genes is changed in MPS cells relative to controls. Specific mechanisms of these regulations remain to be elucidated; however, it was proposed that they reflect secondary and tertiary changes in cellular processes, after primary GAG storage [32]. On the other hand, it has been indicated that severity of MPS symptoms in patients does not simply correlate with GAG levels in organisms of such patients [33].…”

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

“…Therefore, not only dysfunctions of cells caused by physical storage of GAG in lysosomes, but also disturbances in cellular processes, caused by dysregulation of different genes are responsible for cellular disorders observed in MPS. Assumptions on importance in secondary and tertiary cellular changes were reported previously (as summarized and discussed recently [40]); however, they were not linked to global changes in genes' expression, and all types of MPS were not investigated in this aspect previously. Our results point to possible molecular mechanisms of both common features of MPS and variability between particular MPS types, indicating the way to study this problem in more detail, to find precise causes of changed gene expression and disturbances of cellular processes.…”

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

“…This may indicate that the pathogenesis of LSDs is not limited to the primary cause—accumulation of the storage material. Such a hypothesis can be corroborated by recently published results demonstrating dysregulation of expression of hundreds of genes, coding for proteins involved in various cellular processes, in fibroblasts derived from patients suffering from mucopolysaccharidoses [ 51 , 106 , 107 , 108 , 109 , 110 , 111 ].…”

“…In fact, changes in ferroptosis efficiency arising from modulation of lysosomal activities have been suggested [ 3 ]. As mentioned in the introduction, various therapeutic strategies for LSD have been tested; however, apart from the non-neuronopathic type of Gaucher disease, no abolition of symptoms could be achieved in severe and neuronopathic forms of these diseases, and only partial improvement could be achieved in milder forms [ 51 , 52 , 53 ].…”