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Special Issue "Molecular Features of Lysosomal Storage Disorders"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 September 2018).

Special Issue Editor

Prof. Dr. Ritva Tikkanen
E-Mail Website1 Website2
Guest Editor
Institute of Biochemistry, Medical Faculty, Justus-Liebig University of Giessen, Friedrichstrasse 24, D-35392, Giessen, Germany
Interests: lysosomes; matabolic pathways; lysosomal storage disorders; signaling; cell adhesion; endosomal trafficking
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our 2016 Special Issue, “Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond”.

Lysosomal storage disorders (LSDs) are a heterogeneous group of rare monogenic diseases that are characterized by aberrant lysosomes with storage material. These diseases frequently manifest as severe defects of the central nervous system, mental retardation and reduced life span. Most LSDs result from a deficiency of a single enzyme, whereas others are caused by mutations in non-enzymatic proteins. In the past couple of years, our knowledge about the pathogenesis and the molecular details of the genes involved has substantially increased. These findings have forced us to rethink some old central dogmas about these diseases and revealed novel aspects about the pathomechanisms. Importantly, novel therapy options have become available, or are under development, for some LSDs that were previously considered fatal.

The purpose of this Special Issue is to summarize our current understanding about the molecular features of LSDs and the involvement of various cellular pathways, such as autophagy, neuroinflammation, microgliosis and signaling in their pathogenesis. We also highly welcome papers addressing the molecular aspects of current and prospective therapies for LSDs, as well as novel concepts and hypothesis about these disorders, including their connections to more common diseases, such as Alzheimer or Parkinson. However, papers addressing disease phenotypes or clinical studies without a clear molecular emphasis are not within the scope of this issue. We encourage the submission of review articles and original research papers. Our aim is to provide a comprehensive update on LSDs, their pathomechanisms and therapy options at the molecular level.

Prof. Dr. Ritva Tikkanen
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lysosomes
  • lysosomal storage disorders
  • neurodegeneration
  • nanoparticles
  • enzyme replacement
  • gene therapy
  • substrate reduction
  • pharmacological chaperones

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Published Papers (14 papers)

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Research

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Open AccessArticle
In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C
Int. J. Mol. Sci. 2019, 20(5), 1152; https://doi.org/10.3390/ijms20051152 - 06 Mar 2019
Cited by 1
Abstract
Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of [...] Read more.
Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of G2-β-CD as an injectable agent were assessed, and molecular interactions between G2-β-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-β-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-β-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-β-CD formed higher-order inclusion complexes with free cholesterol. G2-β-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-β-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-β-CD (21.4 μmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-β-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling
Int. J. Mol. Sci. 2019, 20(3), 717; https://doi.org/10.3390/ijms20030717 - 07 Feb 2019
Cited by 3
Abstract
The accumulation of lipids in the late endosomes and lysosomes of Niemann–Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 [...] Read more.
The accumulation of lipids in the late endosomes and lysosomes of Niemann–Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel’s voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that phosphoinositides are responsible for both the mislocalization of annexin A2 (AnxA2) and a soluble NSF (N-ethylmaleimide Sensitive Fusion) protein attachment receptor (SNARE) recycling defect. These results are set in the context of existing knowledge of NPCD to sketch an account of the endolysosomal pathology key to this disease. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
The Role of Dimethyl Sulfoxide (DMSO) in Gene Expression Modulation and Glycosaminoglycan Metabolism in Lysosomal Storage Disorders on an Example of Mucopolysaccharidosis
Int. J. Mol. Sci. 2019, 20(2), 304; https://doi.org/10.3390/ijms20020304 - 14 Jan 2019
Cited by 1
Abstract
Obstacles to effective therapies for mucopolysaccharidoses (MPSs) determine the need for continuous studies in order to enhance therapeutic strategies. Dimethyl sulfoxide (DMSO) is frequently utilised as a solvent in biological studies, and as a vehicle for drug therapy and the in vivo administration [...] Read more.
Obstacles to effective therapies for mucopolysaccharidoses (MPSs) determine the need for continuous studies in order to enhance therapeutic strategies. Dimethyl sulfoxide (DMSO) is frequently utilised as a solvent in biological studies, and as a vehicle for drug therapy and the in vivo administration of water-insoluble substances. In the light of the uncertainty on the mechanisms of DMSO impact on metabolism of glycosaminoglycans (GAGs) pathologically accumulated in MPSs, in this work, we made an attempt to investigate and resolve the question of the nature of GAG level modulation by DMSO, the isoflavone genistein solvent employed previously by our group in MPS treatment. In this work, we first found the cytotoxic effect of DMSO on human fibroblasts at concentrations above 3%. Also, our results displayed the potential role of DMSO in the regulation of biological processes at the transcriptional level, then demonstrated a moderate impact of the solvent on GAG synthesis. Interestingly, alterations of lysosomal ultrastructure upon DMSO treatment were visible. As there is growing evidence in the literature that DMSO can affect cellular pathways leading to numerous changes, it is important to expand our knowledge concerning this issue. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease?
Int. J. Mol. Sci. 2018, 19(12), 3726; https://doi.org/10.3390/ijms19123726 - 23 Nov 2018
Cited by 6
Abstract
Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal [...] Read more.
Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
Gadolinium Chloride Rescues Niemann–Pick Type C Liver Damage
Int. J. Mol. Sci. 2018, 19(11), 3599; https://doi.org/10.3390/ijms19113599 - 14 Nov 2018
Abstract
Niemann–Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with [...] Read more.
Niemann–Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68—A marker of Kupffer cells in the liver—and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
Main Olfactory and Vomeronasal Epithelium Are Differently Affected in Niemann-Pick Disease Type C1
Int. J. Mol. Sci. 2018, 19(11), 3563; https://doi.org/10.3390/ijms19113563 - 12 Nov 2018
Cited by 1
Abstract
Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to [...] Read more.
Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective Npc1 gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. Methods: Proliferation in the VNE and OE was assessed by applying a bromodeoxyuridine (BrdU) protocol. We further compared the immunoreactivities of anti-olfactory marker protein (OMP), and the lysosomal marker cathepsin-D in both epithelia. To investigate if degenerative effects of both olfactory systems can be prevented or reversed, some animals were treated with a combination of miglustat/allopregnanolone/2-hydroxypropyl-cyclodextrin (HPβCD), or a monotherapy with HPβCD alone. Results: Using BrdU to label dividing cells of the VNE, we detected a proliferation increase of 215% ± 12% in Npc1−/− mice, and 270% ± 10% in combination- treated Npc1−/− animals. The monotherapy with HPβCD led to an increase of 261% ± 10.5% compared to sham-treated Npc1−/− mice. Similar to the OE, we assessed the high regenerative potential of vomeronasal progenitor cells. OMP reactivity in the VNE of Npc1−/− mice was not affected, in contrast to that observed in the OE. Concomitantly, cathepsin-D reactivity in the VNE was virtually absent. Conclusion: Vomeronasal receptor neurons are less susceptible against NPC1 pathology than olfactory receptor neurons. Compared to control mice, however, the VNE of Npc1−/− mice displays an increased neuroregenerative potential, indicating compensatory cell renewal. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
A Nationwide Survey on Danon Disease in Japan
Int. J. Mol. Sci. 2018, 19(11), 3507; https://doi.org/10.3390/ijms19113507 - 08 Nov 2018
Cited by 2
Abstract
Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, [...] Read more.
Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf–Parkinson–White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways
Int. J. Mol. Sci. 2018, 19(9), 2623; https://doi.org/10.3390/ijms19092623 - 04 Sep 2018
Cited by 1
Abstract
The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1–NPC2 protein–protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal [...] Read more.
The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1–NPC2 protein–protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal (LE)/lysosomal (Lys) compartments. Mutations in either NPC1 or NPC2 can lead to an accumulation of cholesterol and lipids in the LE/Lys, the primary phenotype of the NPC disease. We investigated the NPC1(NTD)–NPC2 protein–protein complex computationally using two putative binding interfaces. A combination of molecular modeling and molecular dynamics simulations reveals atomic details that are responsible for interface stability. Cholesterol binding energies associated with each of the binding pockets for the two models are calculated. Analyses of the cholesterol binding in the two models support bidirectional ligand transfer when a particular interface is established. Based on the results, we propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1(NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD). Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessArticle
Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis
Int. J. Mol. Sci. 2018, 19(2), 625; https://doi.org/10.3390/ijms19020625 - 22 Feb 2018
Cited by 3
Abstract
Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically [...] Read more.
Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically accurate mouse model (Cln3Δex7/8 mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3Δex7/8 mice, we have here analyzed the consequences of the CLN3 deletion on levels of cellular gangliosides, particularly GM3, GM2, GM1a and GD1a. The levels of GM1a and GD1a were found to be significantly reduced by both biochemical and cytochemical methods. However, quantitative high-performance liquid chromatography analysis revealed a highly significant increase in GM3, suggesting a metabolic blockade in the conversion of GM3 to more complex gangliosides. Quantitative real-time PCR analysis revealed a significant reduction in the transcripts of the interconverting enzymes, especially of β-1,4-N-acetyl-galactosaminyl transferase 1 (GM2 synthase), which is the enzyme converting GM3 to GM2. Thus, our data suggest that the complex a-series gangliosides are reduced in Cln3Δex7/8 mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Review

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Open AccessReview
Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases
Int. J. Mol. Sci. 2019, 20(2), 327; https://doi.org/10.3390/ijms20020327 - 15 Jan 2019
Cited by 1
Abstract
Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main [...] Read more.
Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main molecular pathways known so far to be involved in the pathogenesis of the disease. A literature search was conducted using the Medline/PubMed and EMBASE databases to identify studies, from 1968 through to November 2018, that investigated the respiratory manifestations and molecular pathways affected in LSD. Pulmonary involvement includes interstitial lung disease in Gaucher’s disease and Niemann-Pick disease, obstructive airway disease in Fabry disease and ventilatory disorders with chronic respiratory failure in Pompe disease due to diaphragmatic and abdominal wall muscle weakness. In mucopolysaccharidosis and mucolipidoses, respiratory symptoms usually manifest early in life and are secondary to anatomical malformations, particularly of the trachea and chest wall, and to accumulation of glycosaminoglycans in the upper and lower airways, causing, for example, obstructive sleep apnea syndrome. Although the molecular pathways involved vary, ranging from lipid to glycogen and glycosaminoglycans accumulation, some clinical manifestations and therapeutic approaches are common among diseases, suggesting that lysosomal storage and subsequent cellular toxicity are the common endpoints. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessReview
Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages
Int. J. Mol. Sci. 2019, 20(1), 66; https://doi.org/10.3390/ijms20010066 - 24 Dec 2018
Cited by 4
Abstract
Several diseases are caused by inherited defects in lysosomes, the so-called lysosomal storage disorders (LSDs). In some of these LSDs, tissue macrophages transform into prominent storage cells, as is the case in Gaucher disease. Here, macrophages become the characteristic Gaucher cells filled with [...] Read more.
Several diseases are caused by inherited defects in lysosomes, the so-called lysosomal storage disorders (LSDs). In some of these LSDs, tissue macrophages transform into prominent storage cells, as is the case in Gaucher disease. Here, macrophages become the characteristic Gaucher cells filled with lysosomes laden with glucosylceramide, because of their impaired enzymatic degradation. Biomarkers of Gaucher cells were actively searched, particularly after the development of costly therapies based on enzyme supplementation and substrate reduction. Proteins selectively expressed by storage macrophages and secreted into the circulation were identified, among which glycoprotein non-metastatic protein B (GPNMB). This review focusses on the emerging potential of GPNMB as a biomarker of stressed macrophages in LSDs as well as in acquired pathologies accompanied by an excessive lysosomal substrate load in macrophages. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Open AccessReview
Pain in Mucopolysaccharidoses: Analysis of the Problem and Possible Treatments
Int. J. Mol. Sci. 2018, 19(10), 3063; https://doi.org/10.3390/ijms19103063 - 08 Oct 2018
Cited by 1
Abstract
Mucopolysaccharidosis (MPS) are a group of lysosomal storage disorders that are caused by the deficiency of enzymes involving in the catabolism of glycosaminoglycan (GAGs). GAGs incompletely degraded accumulate in many sites, damaging tissues and cells, leading to a variety of clinical manifestations. Many [...] Read more.
Mucopolysaccharidosis (MPS) are a group of lysosomal storage disorders that are caused by the deficiency of enzymes involving in the catabolism of glycosaminoglycan (GAGs). GAGs incompletely degraded accumulate in many sites, damaging tissues and cells, leading to a variety of clinical manifestations. Many of these manifestations are painful, but few data are available in the literature concerning the prevalence, etiology, and pathogenesis of pain in children with MPS. This review, through the analysis of the data available the in literature, underscores the relevant prevalence of pain in MPSs’ children, provides the instruments to discern the etiopathogenesis of the disease and of pain, illustrates the available molecules for the management of pain and the possible advantages of non-pharmacological pain therapy in MPSs’ patients. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)

Other

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Open AccessComment
Macroglossia, Motor Neuron Pathology, and Airway Malacia Contribute to Respiratory Insufficiency in Pompe Disease: A Commentary on Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases
Int. J. Mol. Sci. 2019, 20(3), 751; https://doi.org/10.3390/ijms20030751 - 11 Feb 2019
Cited by 1
Abstract
The authors of the recently published, “Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases”, provide an important review of the various mechanisms of lysosomal storage diseases (LSD) and how they culminate in similar clinical pathologies [...] Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
Open AccessBrief Report
In Silico Analysis of Missense Mutations as a First Step in Functional Studies: Examples from Two Sphingolipidoses
Int. J. Mol. Sci. 2018, 19(11), 3409; https://doi.org/10.3390/ijms19113409 - 31 Oct 2018
Abstract
In order to delineate a better approach to functional studies, we have selected 23 missense mutations distributed in different domains of two lysosomal enzymes, to be studied by in silico analysis. In silico analysis of mutations relies on computational modeling to predict their [...] Read more.
In order to delineate a better approach to functional studies, we have selected 23 missense mutations distributed in different domains of two lysosomal enzymes, to be studied by in silico analysis. In silico analysis of mutations relies on computational modeling to predict their effects. Various computational platforms are currently available to check the probable causality of mutations encountered in patients at the protein and at the RNA levels. In this work we used four different platforms freely available online (Protein Variation Effect Analyzer- PROVEAN, PolyPhen-2, Swiss-model Expert Protein Analysis System—ExPASy, and SNAP2) to check amino acid substitutions and their effect at the protein level. The existence of functional studies, regarding the amino acid substitutions, led to the selection of the distinct protein mutants. Functional data were used to compare the results obtained with different bioinformatics tools. With the advent of next-generation sequencing, it is not feasible to carry out functional tests in all the variants detected. In silico analysis seems to be useful for the delineation of which mutants are worth studying through functional studies. Therefore, prediction of the mutation impact at the protein level, applying computational analysis, confers the means to rapidly provide a prognosis value to genotyping results, making it potentially valuable for patient care as well as research purposes. The present work points to the need to carry out functional studies in mutations that might look neutral. Moreover, it should be noted that single nucleotide polymorphisms (SNPs), occurring in coding and non-coding regions, may lead to RNA alterations and should be systematically verified. Functional studies can gain from a preliminary multi-step approach, such as the one proposed here. Full article
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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