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Special Issue "Genetic and Metabolic Molecular Research of Lysosomal Storage Disease"

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 (31 December 2020).

Special Issue Editor

Special Issue Information

Lysosomal storage diseases (LSD) is a group of inherited metabolic disorders in which defects of various lysosomal enzymes and regulatory proteins result in accumulation of different macromolecules in these orgnella. There are over 50 LSD described in the literature, and they are among the most intensively studied genetic disorders. In fact, they are also model genetic diseases for development of various therapeutic approaches. Introduction of enzyme replacement therapy for LSD was a breakthrough is treating genetic diseases, and several different therapeutic options are currently studied, including hematopoietic stem cell transplantation, gene therapy, substrate reduction therapy and others. However, to develop new therapies, molecular mechanisms of LSD must be understood in great deatils. In fact, now there is a time for extensive molecular research on LSD. This special issue is devoted to publish results of such studies, includind basic research on molecular mechanisms of LSD, translational studies on novel therapies and clinical investigations performed at molecular level. Review articles on all these aspects are also welcome. It is, threrfore, expected that this special issue should provide a comprehensive view on molecular aspects of various LSD. Although pathophysiology, mechanism and terapeutic strategies of lysosomal storage diseases were topics covered by another special issue of IJMS, this issue is devoted to present research on molecular aspects of these diseases. The editors consider that this group of diseases is a forefront of genetic and metabolic disorders which are studied on molecular level, and our understanding of molecular mechanisms, molecular pharmacology and clinical aspects on molecular level are crucial for further research in this field, as well as for opening new ways of thinking about other, currently less understood, diseases.

Prof. Dr. Grzegorz Wegrzyn
Guest Editor

Manuscript Submission Information

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Keywords

  • Lysosomal storage diseases
  • molecular mechanisms of genetic disorders
  • metabolic diseases
  • accumulation of macromolecules in cells
  • enzyme replacement therapy
  • hematopoietic stem cell transplantation
  • gene therapy
  • substrate reduction therapy
  • translational research
  • novel therapies for genetic diseases

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Published Papers (8 papers)

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Research

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Article
Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses
Int. J. Mol. Sci. 2021, 22(5), 2766; https://doi.org/10.3390/ijms22052766 - 09 Mar 2021
Viewed by 518
Abstract
Mucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by accumulation of incompletely degraded glycosaminoglycans (GAGs) in lysosomes. Although primary causes of these diseases are mutations in genes coding for enzymes involved in lysosomal GAG degradation, it was demonstrated that storage of these complex carbohydrates [...] Read more.
Mucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by accumulation of incompletely degraded glycosaminoglycans (GAGs) in lysosomes. Although primary causes of these diseases are mutations in genes coding for enzymes involved in lysosomal GAG degradation, it was demonstrated that storage of these complex carbohydrates provokes a cascade of secondary and tertiary changes affecting cellular functions. Potentially, this might lead to appearance of cellular disorders which could not be corrected even if the primary cause of the disease is removed. In this work, we studied changes in cellular organelles in MPS fibroblasts relative to control cells. All 11 types and subtypes of MPS were included into this study to obtain a complex picture of changes in organelles in this group of diseases. Two experimental approaches were employed, transcriptomic analyses and electron microscopic assessment of morphology of organelles. We analyzed levels of transcripts of genes grouped into two terms included into the QuickGO database, ‘Cellular component organization’ (GO:0016043) and ‘Cellular anatomical entity’ (GO:0110165), to find that number of transcripts with significantly changed levels in MPS fibroblasts vs. controls ranged from 109 to 322 (depending on MPS type) in GO:0016043, and from 70 to 208 in GO:0110165. This dysregulation of expression of genes crucial for proper structures and functions of various organelles was accompanied by severe changes in morphologies of lysosomes, nuclei, mitochondria, Golgi apparatus, and endoplasmic reticulum. Interestingly, some observed changes occurred in all/most MPS types while others were specific to particular disease types/subtypes. We suggest that severe changes in organelles in MPS cells might arise from dysregulation of expression of a battery of genes involved in organelles’ structures and functions. Intriguingly, normalization of GAG levels by using recombinant human enzymes specific to different MPS types corrected morphologies of some, but not all, organelles, while it failed to improve regulation of expression of selected genes. These results might suggest reasons for inability of enzyme replacement therapy to correct all MPS symptoms, particularly if initiated at advanced stages of the disease. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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Article
A Possible Role for Arylsulfatase G in Dermatan Sulfate Metabolism
Int. J. Mol. Sci. 2020, 21(14), 4913; https://doi.org/10.3390/ijms21144913 - 12 Jul 2020
Viewed by 821
Abstract
Perturbations of glycosaminoglycan metabolism lead to mucopolysaccharidoses (MPS)—lysosomal storage diseases. One type of MPS (type VI) is associated with a deficiency of arylsulfatase B (ARSB), for which we previously established a cellular model using pulmonary artery endothelial cells with a silenced ARSB gene. [...] Read more.
Perturbations of glycosaminoglycan metabolism lead to mucopolysaccharidoses (MPS)—lysosomal storage diseases. One type of MPS (type VI) is associated with a deficiency of arylsulfatase B (ARSB), for which we previously established a cellular model using pulmonary artery endothelial cells with a silenced ARSB gene. Here, we explored the effects of silencing the ARSB gene on the growth of human pulmonary artery smooth muscle cells in the presence of different concentrations of dermatan sulfate (DS). The viability of pulmonary artery smooth muscle cells with a silenced ARSB gene was stimulated by the dermatan sulfate. In contrast, the growth of pulmonary artery endothelial cells was not affected. As shown by microarray analysis, the expression of the arylsulfatase G (ARSG) in pulmonary artery smooth muscle cells increased after silencing the arylsulfatase B gene, but the expression of genes encoding other enzymes involved in the degradation of dermatan sulfate did not. The active site of arylsulfatase G closely resembles that of arylsulfatase B, as shown by molecular modeling. Together, these results lead us to propose that arylsulfatase G can take part in DS degradation; therefore, it can affect the functioning of the cells with a silenced arylsulfatase B gene. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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Article
Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism
Int. J. Mol. Sci. 2020, 21(12), 4211; https://doi.org/10.3390/ijms21124211 - 12 Jun 2020
Cited by 6 | Viewed by 890
Abstract
Mucopolysaccharidoses (MPSs) are inherited disorders of the glycosaminoglycan (GAG) metabolism. The defective digestion of GAGs within the intralysosomal compartment of affected patients leads to a broad spectrum of clinical manifestations ranging from cardiovascular disease to neurological impairment. The molecular mechanisms underlying the progression [...] Read more.
Mucopolysaccharidoses (MPSs) are inherited disorders of the glycosaminoglycan (GAG) metabolism. The defective digestion of GAGs within the intralysosomal compartment of affected patients leads to a broad spectrum of clinical manifestations ranging from cardiovascular disease to neurological impairment. The molecular mechanisms underlying the progression of the disease downstream of the genetic mutation of genes encoding for lysosomal enzymes still remain unclear. Here, we applied a targeted metabolomic approach to a mouse model of PS IIIB, using a platform dedicated to the diagnosis of inherited metabolic disorders, in order to identify amino acid and fatty acid metabolic pathway alterations or the manifestations of other metabolic phenotypes. Our analysis highlighted an increase in the levels of branched-chain amino acids (BCAAs: Val, Ile, and Leu), aromatic amino acids (Tyr and Phe), free carnitine, and acylcarnitines in the liver and heart tissues of MPS IIIB mice as compared to the wild type (WT). Moreover, Ala, Met, Glu, Gly, Arg, Orn, and Cit amino acids were also found upregulated in the liver of MPS IIIB mice. These findings show a specific impairment of the BCAA and fatty acid catabolism in the heart of MPS IIIB mice. In the liver of affected mice, the glucose-alanine cycle and urea cycle resulted in being altered alongside a deregulation of the BCAA metabolism. Thus, our data demonstrate that an accumulation of BCAAs occurs secondary to lysosomal GAG storage, in both the liver and the heart of MPS IIIB mice. Since BCAAs regulate the biogenesis of lysosomes and autophagy mechanisms through mTOR signaling, impacting on lipid metabolism, this condition might contribute to the progression of the MPS IIIB disease. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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Review

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Review
Fabry Disease Therapy: State-of-the-Art and Current Challenges
Int. J. Mol. Sci. 2021, 22(1), 206; https://doi.org/10.3390/ijms22010206 - 28 Dec 2020
Cited by 1 | Viewed by 891
Abstract
Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the [...] Read more.
Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that “in vitro” amenability may not always reflect “in vivo” amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
Review
Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches
Int. J. Mol. Sci. 2020, 21(21), 7819; https://doi.org/10.3390/ijms21217819 - 22 Oct 2020
Cited by 1 | Viewed by 832
Abstract
Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in [...] Read more.
Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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Review
Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review
Int. J. Mol. Sci. 2020, 21(19), 7159; https://doi.org/10.3390/ijms21197159 - 28 Sep 2020
Cited by 5 | Viewed by 1056
Abstract
The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for [...] Read more.
The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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Review
GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
Int. J. Mol. Sci. 2020, 21(17), 6213; https://doi.org/10.3390/ijms21176213 - 27 Aug 2020
Cited by 4 | Viewed by 1591
Abstract
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the [...] Read more.
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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Review
Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV—A Review and Case Series
Int. J. Mol. Sci. 2020, 21(12), 4564; https://doi.org/10.3390/ijms21124564 - 26 Jun 2020
Cited by 2 | Viewed by 846
Abstract
Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal storage disorder caused by biallelic mutations in MCOLN1 gene encoding the transient receptor potential channel mucolipin-1. So far, 35 pathogenic or likely pathogenic MLIV-related variants have been described. Clinical manifestations include severe intellectual disability, speech [...] Read more.
Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal storage disorder caused by biallelic mutations in MCOLN1 gene encoding the transient receptor potential channel mucolipin-1. So far, 35 pathogenic or likely pathogenic MLIV-related variants have been described. Clinical manifestations include severe intellectual disability, speech deficit, progressive visual impairment leading to blindness, and myopathy. The severity of the condition may vary, including less severe psychomotor delay and/or ocular findings. As no striking recognizable facial dysmorphism, skeletal anomalies, organomegaly, or lysosomal enzyme abnormalities in serum are common features of MLIV, the clinical diagnosis may be significantly improved because of characteristic ophthalmological anomalies. This review aims to outline the pathophysiology and genetic defects of this condition with a focus on the genotype–phenotype correlation amongst cases published in the literature. The authors will present their own clinical observations and long-term outcomes in adult MLIV cases. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
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