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Pathophysiology, Molecular Mechanism and Therapeutic Strategies of Lysosomal Storage Disorders (LSD)

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 (1 May 2021) | Viewed by 47034

Special Issue Editors

1. Gaucher Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel
2. Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Interests: gaucher disease; pediatric hematology; pediatric thrombosis and hemostasis; platelet disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Friends and Colleagues,

It gives us a pleasure to invite you to submit a paper to the forthcoming Special Issue of the International Journal of Molecular Sciences (IJMS) on Lysosomal Storage Disorders (LSD).

The IJMS is an open access, peer-reviewed journal with an IF of 4.18, and in the Special Issue on LSD, we welcome any high-quality contribution, which could be research articles from basic science to clinical studies, and we also invite reviews and case studies, with a common purpose to expand the current knowledge in this important area of LSDs. While, as 70 inherited metabolic disorders, they are considered rare, as a group, their incidence is about 1:5000, and they are all the more important given the many different types of underlying lysosomal dysfunction. In addition to the accumulation of the unmetabolized substrate (hence the concept of “storage” disorders), there are a variety of cellular and subcellular abnormalities, including endoplasmic reticulum stress, altered lipid trafficking, autophagy, inflammation, and autoimmune responses. Each of these pathological processes, alone or in combination, may lead to the development of novel therapeutic modalities, some of which have already changed natural history and the lives of patients with various diseases, such as Gaucher, Fabry, MPS and others, and in addition, these new treatments, including gene therapy, may also be of relevance to more common disorders, as we have witnessed from the relationship between Gaucher (both patients and carriers) and Parkinson’s diseases.

We would appreciate the submission of your contributions within the next 3 months, allowing us to get the full issue in print at the first quarter of 2020.

Prof. Ari Zimran
Prof. Shoshana Revel-Vilk
Guest Editors

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

  • LSDs
  • lysosomal storage disorders
  • lysosomal dysfunction
  • endoplasmic reticulum stress
  • altered lipid trafficking
  • autophagy
  • inflammation
  • enzyme therapy
  • substrate reduction
  • pharmacological chaperones
  • gene therapy

Published Papers (14 papers)

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Research

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16 pages, 1550 KiB  
Article
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages
by Jacquelyn C. Serfecz, Afsoon Saadin, Clayton P. Santiago, Yuji Zhang, Søren M. Bentzen, Stefanie N. Vogel and Ricardo A. Feldman
Int. J. Mol. Sci. 2021, 22(18), 9912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189912 - 14 Sep 2021
Cited by 14 | Viewed by 2641
Abstract
Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of [...] Read more.
Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD. Full article
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11 pages, 1826 KiB  
Article
Impact of Long-Term Enzyme Replacement Therapy on Glucosylsphingosine (Lyso-Gb1) Values in Patients with Type 1 Gaucher Disease: Statistical Models for Comparing Three Enzymatic Formulations
by Tama Dinur, Ulrike Grittner, Shoshana Revel-Vilk, Michal Becker-Cohen, Majdolen Istaiti, Claudia Cozma, Arndt Rolfs and Ari Zimran
Int. J. Mol. Sci. 2021, 22(14), 7699; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147699 - 19 Jul 2021
Cited by 11 | Viewed by 3581
Abstract
For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond [...] Read more.
For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker). A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT (imiglucerase (n = 41, 30.4%), taliglucerase alfa (n = 21, 15.6%) and velaglucerase alfa (n = 73, 54.1%)), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index (SSI; mild: <7; severe: ≥7). Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions. Full article
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11 pages, 1563 KiB  
Article
Behavioral Phenotyping in a Murine Model of GBA1-Associated Parkinson Disease
by Jenny Do, Gani Perez, Bahafta Berhe, Nahid Tayebi and Ellen Sidransky
Int. J. Mol. Sci. 2021, 22(13), 6826; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136826 - 25 Jun 2021
Cited by 3 | Viewed by 2114
Abstract
Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we [...] Read more.
Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled GBA1-associated PD by crossing gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether gba+/−//SNCAA53T mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of gba+///SNCAA53T (n = 8), SNCAA53T (n = 9), gba+/ (n = 10) and wildtype (n = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old gba+///SNCAA53T mice showed more olfactory and motor deficits than wildtype mice. However, differences between gba+///SNCAA53T and SNCAA53T mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while gba haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course. Full article
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11 pages, 1225 KiB  
Communication
Accurate Molecular Diagnosis of Gaucher Disease Using Clinical Exome Sequencing as a First-Tier Test
by Stefania Zampieri, Silvia Cattarossi, Eleonora Pavan, Antonio Barbato, Agata Fiumara, Paolo Peruzzo, Maurizio Scarpa, Giovanni Ciana and Andrea Dardis
Int. J. Mol. Sci. 2021, 22(11), 5538; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115538 - 24 May 2021
Cited by 3 | Viewed by 2178
Abstract
Gaucher disease (GD) is an autosomal recessive lysosomal disorder due to beta-glucosidase gene (GBA) mutations. The molecular diagnosis of GD is complicated by the presence of recombinant alleles originating from a highly homologous pseudogene. Clinical exome sequencing (CES) is a rapid [...] Read more.
Gaucher disease (GD) is an autosomal recessive lysosomal disorder due to beta-glucosidase gene (GBA) mutations. The molecular diagnosis of GD is complicated by the presence of recombinant alleles originating from a highly homologous pseudogene. Clinical exome sequencing (CES) is a rapid genetic approach for identifying disease-causing mutations. However, copy number variation and recombination events are poorly detected, and further investigations are required to avoid mis-genotyping. The aim of this work was to set-up an integrated strategy for GD patients genotyping using CES as a first-line test. Eight patients diagnosed with GD were analyzed by CES. Five patients were fully genotyped, while three were revealed to be homozygous for mutations that were not confirmed in the parents. Therefore, MLPA (multiplex ligation-dependent probe amplification) and specific long-range PCR were performed, and two recombinant alleles, one of them novel, and one large deletion were identified. Furthermore, an MLPA assay performed in one family resulted in the identification of an additional novel mutation (p.M124V) in a relative, in trans with the known p.N409S mutation. In conclusion, even though CES has become extensively used in clinical practice, our study emphasizes the importance of a comprehensive molecular strategy to provide proper GBA genotyping and genetic counseling. Full article
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15 pages, 8984 KiB  
Article
GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice
by Martijn J. C. van der Lienden, Jan Aten, André R. A. Marques, Ingeborg S. E. Waas, Per W. B. Larsen, Nike Claessen, Nicole N. van der Wel, Roelof Ottenhoff, Marco van Eijk and Johannes M. F. G. Aerts
Int. J. Mol. Sci. 2021, 22(5), 2532; https://doi.org/10.3390/ijms22052532 - 03 Mar 2021
Cited by 6 | Viewed by 3364
Abstract
The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show [...] Read more.
The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old Npc1−/− mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In Npc1−/− liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in Npc1−/− liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the Npc1−/− liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in Npc1−/− hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes. Full article
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10 pages, 1746 KiB  
Article
The Interaction of Innate and Adaptive Immunity and Stabilization of Mast Cell Activation in Management of Infusion Related Reactions in Patients with Fabry Disease
by Renuka P. Limgala, Jaqueline Fikry, Vasudha Veligatla and Ozlem Goker-Alpan
Int. J. Mol. Sci. 2020, 21(19), 7213; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197213 - 29 Sep 2020
Cited by 1 | Viewed by 2936
Abstract
Fabry disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA gene resulting in lack of or faulty α-galactosidase A (α-GalA) enzyme. Enzyme replacement therapy (ERT) with recombinant human α-GalA enzyme (agalsidase) is the standard treatment option for FD. Infusion-related reactions [...] Read more.
Fabry disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA gene resulting in lack of or faulty α-galactosidase A (α-GalA) enzyme. Enzyme replacement therapy (ERT) with recombinant human α-GalA enzyme (agalsidase) is the standard treatment option for FD. Infusion-related reactions (IRRs), with symptoms ranging from rigors, to fever, pain, vomiting, angioedema and diarrhea, are often seen due to immune response against the exogenous enzyme. To elucidate the mechanisms causing the IRRs in FD, eight patients who developed IRRs were investigated. All, except one, tested negative for agalsidase-specific IgE and had normal tryptase levels. Circulating dendritic cells were drastically reduced during IRRs, suggesting possible sequestration to the sites of inflammation. An increase in NK cells and a decrease in T cells were also observed. Cytokines IL-4, IL-8 and TNF-α showed a significant increase, indicating nonspecific degranulation of mast cells. All IRRs were managed successfully using a combination of standard premedications and mast cell stabilizers without any interruption of therapy. Taken together, the results indicate crosstalk between immune cells resulting in IgE-independent mast-cell-specific allergic inflammation. Mast cell stabilizers could be used to control IRRs and for safe reintroduction of agalsidase in patients previously treated with ERT. Full article
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9 pages, 1200 KiB  
Communication
Macular Ganglion Cell Complex and Peripapillary Retinal Nerve Fiber Layer Thinning in Patients with Type-1 Gaucher Disease
by Yishay Weill, Ari Zimran, David Zadok, Lauren M. Wasser, Shoshana Revel-Vilk, Joel Hanhart, Tama Dinur, David Arkadir and Michal Becker-Cohen
Int. J. Mol. Sci. 2020, 21(19), 7027; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197027 - 24 Sep 2020
Cited by 2 | Viewed by 2765
Abstract
Type-1 Gaucher disease (GD1) is considered to be non- neuronopathic however recent evidence of neurological involvement continues to accumulate. There is limited evidence of retinal abnormalities in GD1. The purpose of this study was to evaluate the retinal findings of patients with GD1. [...] Read more.
Type-1 Gaucher disease (GD1) is considered to be non- neuronopathic however recent evidence of neurological involvement continues to accumulate. There is limited evidence of retinal abnormalities in GD1. The purpose of this study was to evaluate the retinal findings of patients with GD1. Thirty GD1 individuals and 30 healthy volunteers between the ages 40–75 years were prospectively enrolled. Macular and optic nerve optical coherence tomography (OCT) scans of both eyes of each patient were performed and thickness maps were compared between groups. Patients with a known neurodegenerative disease, glaucoma, high myopia and previous intraocular surgeries were excluded. It was shown that patients with GD1 presented with higher incidence of abnormal pRNFL OCT scan and showed significantly thinner areas of pRNFL and macular ganglion cell complex (GCC) when compared to a healthy control population. Changes in retinal thickness were not associated with GD1 genotype, treatment status, disease monitoring biomarker (lyso-Gb1) and severity score index (Zimran SSI). Further investigations are needed to determine whether these findings possess functional visual implications and if retinal thinning may serve as biomarker for the development of future neurodegenerative disease in this population. Full article
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18 pages, 4067 KiB  
Article
Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants
by Marisa Encarnação, Maria Francisca Coutinho, Lisbeth Silva, Diogo Ribeiro, Souad Ouesleti, Teresa Campos, Helena Santos, Esmeralda Martins, Maria Teresa Cardoso, Laura Vilarinho and Sandra Alves
Int. J. Mol. Sci. 2020, 21(17), 6355; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176355 - 01 Sep 2020
Cited by 7 | Viewed by 2875
Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, [...] Read more.
Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients. Full article
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9 pages, 1379 KiB  
Article
Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots
by Claudia Cozma, Paskal Cullufi, Guido Kramp, Marina Hovakimyan, Virtut Velmishi, Agim Gjikopulli, Sonila Tomori, Steffen Fischer, Sebastian Oppermann, Ulrike Grittner, Peter Bauer, Christian Beetz and Arndt Rolfs
Int. J. Mol. Sci. 2020, 21(13), 4577; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134577 - 27 Jun 2020
Cited by 24 | Viewed by 2941
Abstract
Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether [...] Read more.
Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay’s longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the “under treatment” versus “not under treatment” conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients. Full article
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16 pages, 1875 KiB  
Article
CRISPR/Cas9 Editing for Gaucher Disease Modelling
by Eleonora Pavan, Maximiliano Ormazabal, Paolo Peruzzo, Emilio Vaena, Paula Rozenfeld and Andrea Dardis
Int. J. Mol. Sci. 2020, 21(9), 3268; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093268 - 05 May 2020
Cited by 13 | Viewed by 4321
Abstract
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the acid β-glucosidase gene (GBA1). Besides causing GD, GBA1 mutations constitute the main genetic risk factor for developing Parkinson’s disease. The molecular basis of neurological manifestations in [...] Read more.
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the acid β-glucosidase gene (GBA1). Besides causing GD, GBA1 mutations constitute the main genetic risk factor for developing Parkinson’s disease. The molecular basis of neurological manifestations in GD remain elusive. However, neuroinflammation has been proposed as a key player in this process. We exploited CRISPR/Cas9 technology to edit GBA1 in the human monocytic THP-1 cell line to develop an isogenic GD model of monocytes and in glioblastoma U87 cell lines to generate an isogenic GD model of glial cells. Both edited (GBA1 mutant) cell lines presented low levels of mutant acid β-glucosidase expression, less than 1% of residual activity and massive accumulation of substrate. Moreover, U87 GBA1 mutant cells showed that the mutant enzyme was retained in the ER and subjected to proteasomal degradation, triggering unfolded protein response (UPR). U87 GBA1 mutant cells displayed an increased production of interleukin-1β, both with and without inflammosome activation, α-syn accumulation and a higher rate of cell death in comparison with wild-type cells. In conclusion, we developed reliable, isogenic, and easy-to-handle cellular models of GD obtained from commercially accessible cells to be employed in GD pathophysiology studies and high-throughput drug screenings. Full article
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15 pages, 4771 KiB  
Article
Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease
by Stefan Hintze, Sarah Limmer, Paulina Dabrowska-Schlepp, Birgit Berg, Nicola Krieghoff, Andreas Busch, Andreas Schaaf, Peter Meinke and Benedikt Schoser
Int. J. Mol. Sci. 2020, 21(7), 2642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072642 - 10 Apr 2020
Cited by 13 | Viewed by 4229
Abstract
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and [...] Read more.
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and the nervous system. Replacement therapy with the currently approved enzyme relies on M6P-mediated endocytosis. However, therapeutic outcomes still leave room for improvement, especially with regard to skeletal muscles. We tested the uptake, activity, and effect on glucose metabolism of a non-phosphorylated recombinant human GAA produced in moss (moss-GAA). Three variants of moss-GAA differing in glycosylation pattern have been analyzed: two with terminal mannose residues in a paucimannosidic (Man3) or high-mannose (Man 5) configuration and one with terminal N-acetylglucosamine residues (GnGn). Compared to alglucosidase alfa the moss-GAA GnGn variant showed increased uptake in differentiated myotubes. Moreover, incubation of immortalized muscle cells of Gaa−/− mice with moss-GAA GnGn led to similarly efficient clearance of accumulated glycogen as with alglucosidase alfa. These initial data suggest that M6P-residues might not always be necessary for the cellular uptake in enzyme replacement therapy (ERT) and indicate the potential of moss-GAA GnGn as novel alternative drug for targeting skeletal muscle in Pompe patients. Full article
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16 pages, 1939 KiB  
Article
Immunoglobulin Abnormalities in Gaucher Disease: an Analysis of 278 Patients Included in the French Gaucher Disease Registry
by Yann Nguyen, Jérôme Stirnemann, Florent Lautredoux, Bérengère Cador, Monia Bengherbia, Karima Yousfi, Dalil Hamroun, Leonardo Astudillo, Thierry Billette de Villemeur, Anaïs Brassier, Fabrice Camou, Florence Dalbies, Dries Dobbelaere, Francis Gaches, Vanessa Leguy-Seguin, Agathe Masseau, Yves-Marie Pers, Samia Pichard, Christine Serratrice, Marc G. Berger, Bruno Fantin, Nadia Belmatoug and on behalf of the French Evaluation of Gaucher Disease Treatment Committeeadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2020, 21(4), 1247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041247 - 13 Feb 2020
Cited by 16 | Viewed by 3141
Abstract
Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study [...] Read more.
Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (> 30 vs. ≤30 years, HR 4.71, 95%CI [2.40–9.27]; p < 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur. Full article
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Review

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34 pages, 2014 KiB  
Review
Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach
by Maria Francisca Coutinho, Juliana Inês Santos, Liliana S. Mendonça, Liliana Matos, Maria João Prata, Amália S. Jurado, Maria C. Pedroso de Lima and Sandra Alves
Int. J. Mol. Sci. 2020, 21(16), 5732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165732 - 10 Aug 2020
Cited by 5 | Viewed by 3440
Abstract
More than two thirds of Lysosomal Storage Diseases (LSDs) present central nervous system involvement. Nevertheless, only one of the currently approved therapies has an impact on neuropathology. Therefore, alternative approaches are under development, either addressing the underlying enzymatic defect or its downstream consequences. [...] Read more.
More than two thirds of Lysosomal Storage Diseases (LSDs) present central nervous system involvement. Nevertheless, only one of the currently approved therapies has an impact on neuropathology. Therefore, alternative approaches are under development, either addressing the underlying enzymatic defect or its downstream consequences. Also under study is the possibility to block substrate accumulation upstream, by promoting a decrease of its synthesis. This concept is known as substrate reduction therapy and may be triggered by several molecules, such as small interfering RNAs (siRNAs). siRNAs promote RNA interference, a naturally occurring sequence-specific post-transcriptional gene-silencing mechanism, and may target virtually any gene of interest, inhibiting its expression. Still, naked siRNAs have limited cellular uptake, low biological stability, and unfavorable pharmacokinetics. Thus, their translation into clinics requires proper delivery methods. One promising platform is a special class of liposomes called stable nucleic acid lipid particles (SNALPs), which are characterized by high cargo encapsulation efficiency and may be engineered to promote targeted delivery to specific receptors. Here, we review the concept of SNALPs, presenting a series of examples on their efficacy as siRNA nanodelivery systems. By doing so, we hope to unveil the therapeutic potential of these nanosystems for targeted brain delivery of siRNAs in LSDs. Full article
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12 pages, 740 KiB  
Review
Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease
by Shani Blumenreich, Or B. Barav, Bethan J. Jenkins and Anthony H. Futerman
Int. J. Mol. Sci. 2020, 21(14), 4966; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144966 - 14 Jul 2020
Cited by 20 | Viewed by 5268
Abstract
The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists [...] Read more.
The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD. Full article
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