Biomolecules

Editorial

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3 pages, 187 KiB

Open AccessEditorial

Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches

by Enrico Moro

Biomolecules 2021, 11(7), 964; https://doi.org/10.3390/biom11070964 - 30 Jun 2021

Cited by 4 | Viewed by 2765

Abstract

Lysosomal storage disorders (LSDs) are a group of 60 rare inherited diseases characterized by a heterogeneous spectrum of clinical symptoms, ranging from severe intellectual disabilities, cardiac abnormalities, visceromegaly, and bone deformities to slowly progressive muscle weakness, respiratory insufficiency, eye defects (corneal clouding and [...] Read more.

Lysosomal storage disorders (LSDs) are a group of 60 rare inherited diseases characterized by a heterogeneous spectrum of clinical symptoms, ranging from severe intellectual disabilities, cardiac abnormalities, visceromegaly, and bone deformities to slowly progressive muscle weakness, respiratory insufficiency, eye defects (corneal clouding and retinal degeneration), and skin alterations [...] Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

Research

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10 pages, 1957 KiB

Open AccessArticle

Mucopolysaccharidoses Differential Diagnosis by Mass Spectrometry-Based Analysis of Urine Free Glycosaminoglycans—A Diagnostic Prediction Model

by Francesca D’Avanzo, Alessandra Zanetti, Andrea Dardis, Maurizio Scarpa, Nicola Volpi, Francesco Gatto and Rosella Tomanin

Biomolecules 2023, 13(3), 532; https://doi.org/10.3390/biom13030532 - 15 Mar 2023

Cited by 2 | Viewed by 1624

Abstract

Impaired glycosaminoglycans (GAGs) catabolism may lead to a cluster of rare metabolic and genetic disorders called mucopolysaccharidoses (MPSs). Each subtype is caused by the deficiency of one of the lysosomal hydrolases normally degrading GAGs. Affected tissues accumulate undegraded GAGs in cell lysosomes and [...] Read more.

Impaired glycosaminoglycans (GAGs) catabolism may lead to a cluster of rare metabolic and genetic disorders called mucopolysaccharidoses (MPSs). Each subtype is caused by the deficiency of one of the lysosomal hydrolases normally degrading GAGs. Affected tissues accumulate undegraded GAGs in cell lysosomes and in the extracellular matrix, thus leading to the MPS complex clinical phenotype. Although each MPS may present with recognizable signs and symptoms, these may often overlap between subtypes, rendering the diagnosis difficult and delayed. Here, we performed an exploratory analysis to develop a model that predicts MPS subtypes based on UHPLC-MS/MS measurement of a urine free GAG profile (or GAGome). We analyzed the GAGome of 78 subjects (38 MPS, 37 healthy and 3 with other MPS symptom-overlapping disorders) using a standardized kit in a central-blinded laboratory. We observed several MPS subtype-specific GAGome changes. We developed a multivariable penalized Lasso logistic regression model that attained 91.2% balanced accuracy to distinguish MPS type II vs. III vs. any other subtype vs. not MPS, with sensitivity and specificity ranging from 73.3% to 91.7% and from 98.4% to 100%, depending on the predicted subtype. In conclusion, the urine GAGome was revealed to be useful in accurately discriminating the different MPS subtypes with a single UHPLC-MS/MS run and could serve as a reliable diagnostic test for a more rapid MPS biochemical diagnosis. Full article

(This article belongs to the Special Issue Upscaling the Basic Knowledge of Lysosomal Storage Disorders: Novel Insights into the Pathogenic Mechanisms and Emerging Therapeutic Approaches)

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20 pages, 810 KiB

Open AccessArticle

Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience

by Vincenza Gragnaniello, Alessandro P Burlina, Giulia Polo, Antonella Giuliani, Leonardo Salviati, Giovanni Duro, Chiara Cazzorla, Laura Rubert, Evelina Maines, Dominique P Germain and Alberto B Burlina

Biomolecules 2021, 11(7), 951; https://doi.org/10.3390/biom11070951 - 27 Jun 2021

Cited by 29 | Viewed by 4543

Abstract

Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and [...] Read more.

Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and globotriaosylsphingosine (lyso-Gb₃) assays in dried blood spot through a multiplexed MS/MS assay. Furthermore, we report our experience with long-term follow-up of positive subjects. We screened more than 170,000 newborns and 22 males were confirmed to have a GLA gene variant, with an incidence of 1:7879 newborns. All patients were diagnosed with a variant previously associated with the later-onset phenotype of FD or carried an unclassified variant (four patients) or the likely benign p.Ala143Thr variant. All were asymptomatic at the last visit. Although lyso-Gb₃ is not considered a reliable second tier test for newborn screening, it can simplify the screening algorithm when its levels are elevated at birth. After birth, plasma lyso-Gb₃ is a useful marker for non-invasive monitoring of all positive patients. Our study is the largest reported to date in Europe, and presents data from long-term NBS for FD that reveals the current incidence of FD in northeastern Italy. Our follow-up data describe the early disease course and the trend of plasma lyso-Gb₃ during early childhood. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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14 pages, 647 KiB

Open AccessArticle

The Role of Exosomes in Lysosomal Storage Disorders

by Adenrele M. Gleason, Elizabeth G. Woo, Cindy McKinney and Ellen Sidransky

Biomolecules 2021, 11(4), 576; https://doi.org/10.3390/biom11040576 - 15 Apr 2021

Cited by 16 | Viewed by 5338

Abstract

Exosomes, small membrane-bound organelles formed from endosomal membranes, represent a heterogenous source of biological and pathological biomarkers capturing the metabolic status of a cell. Exosomal cargo, including lipids, proteins, mRNAs, and miRNAs, can either act as inter-cellular messengers or are shuttled for autophagic/lysosomal [...] Read more.

Exosomes, small membrane-bound organelles formed from endosomal membranes, represent a heterogenous source of biological and pathological biomarkers capturing the metabolic status of a cell. Exosomal cargo, including lipids, proteins, mRNAs, and miRNAs, can either act as inter-cellular messengers or are shuttled for autophagic/lysosomal degradation. Most cell types in the central nervous system (CNS) release exosomes, which serve as long and short distance communicators between neurons, astrocytes, oligodendrocytes, and microglia. Lysosomal storage disorders are diseases characterized by the accumulation of partially or undigested cellular waste. The exosomal content in these diseases is intrinsic to each individual disorder. Emerging research indicates that lysosomal dysfunction enhances exocytosis, and hence, in lysosomal disorders, exosomal secretion may play a role in disease pathogenesis. Furthermore, the unique properties of exosomes and their ability to carry cargo between adjacent cells and organs, and across the blood–brain barrier, make them attractive candidates for use as therapeutic delivery vehicles. Thus, understanding exosomal content and function may have utility in the treatment of specific lysosomal storage disorders. Since lysosomal dysfunction and the deficiency of at least one lysosomal enzyme, glucocerebrosidase, is associated with the development of parkinsonism, the study and use of exosomes may contribute to an improved understanding of Parkinson disease, potentially leading to new therapeutics. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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12 pages, 2293 KiB

Open AccessArticle

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

by Ilaria Tonazzini, Chiara Cerri, Ambra Del Grosso, Sara Antonini, Manuela Allegra, Matteo Caleo and Marco Cecchini

Biomolecules 2021, 11(1), 7; https://doi.org/10.3390/biom11010007 - 23 Dec 2020

Cited by 6 | Viewed by 2848

Abstract

Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the [...] Read more.

Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule. Here, we describe morphological and functional alterations in the visual system of the Twitcher (TWI) mouse, the most used animal model of Krabbe disease. We report in vivo electrophysiological recordings showing defective basic functional properties of the TWI primary visual cortex. In particular, we demonstrate a reduced visual acuity and contrast sensitivity, and a delayed visual response. Specific neuropathological alterations are present in the TWI visual cortex, with reduced myelination, increased astrogliosis and microglia activation, and around the whole brain. Finally, we quantify PSY content in the brain and optic nerves by high-pressure liquid chromatography-mass spectrometry methods. An increasing PSY accumulation with time, the characteristic hallmark of KD, is found in both districts. These results represent the first complete characterization of the TWI visual system. Our data set a baseline for an easy testing of potential therapies for this district, which is also dramatically affected in KD patients. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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14 pages, 9420 KiB

Open AccessArticle

Elevated Dkk1 Mediates Downregulation of the Canonical Wnt Pathway and Lysosomal Loss in an iPSC Model of Neuronopathic Gaucher Disease

by Manasa P. Srikanth and Ricardo A. Feldman

Biomolecules 2020, 10(12), 1630; https://doi.org/10.3390/biom10121630 - 3 Dec 2020

Cited by 10 | Viewed by 4880

Abstract

Gaucher Disease (GD), which is the most common lysosomal storage disorder, is caused by bi-allelic mutations in GBA1—a gene that encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The neuronopathic forms of GD (nGD) are characterized by severe neurological abnormalities that arise during gestation [...] Read more.

Gaucher Disease (GD), which is the most common lysosomal storage disorder, is caused by bi-allelic mutations in GBA1—a gene that encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The neuronopathic forms of GD (nGD) are characterized by severe neurological abnormalities that arise during gestation or early in infancy. Using GD-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs), we have previously reported that neuronal cells have neurodevelopmental defects associated with the downregulation of canonical Wnt signaling. In this study, we report that GD NPCs display elevated levels of Dkk1, which is a secreted Wnt antagonist that prevents receptor activation. Dkk1 upregulation in mutant NPCs resulted in an increased degradation of β-catenin, and there was a concomitant reduction in lysosomal numbers. Consistent with these results, incubation of the mutant NPCs with recombinant Wnt3a (rWnt3a) was able to outcompete the excess Dkk1, increasing β-catenin levels and rescuing lysosomal numbers. Furthermore, the incubation of WT NPCs with recombinant Dkk1 (rDkk1) phenocopied the mutant phenotype, recapitulating the decrease in β-catenin levels and lysosomal depletion seen in nGD NPCs. This study provides evidence that downregulation of the Wnt/β-catenin pathway in nGD neuronal cells involves the upregulation of Dkk1. As Dkk1 is an extracellular Wnt antagonist, our results suggest that the deleterious effects of Wnt/β-catenin downregulation in nGD may be ameliorated by the prevention of Dkk1 binding to the Wnt co-receptor LRP6, pointing to Dkk1 as a potential therapeutic target for GBA1-associated neurodegeneration. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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22 pages, 5110 KiB

Open AccessArticle

The Release of a Soluble Glycosylated Protein from Glycogen by Recombinant Lysosomal α-Glucosidase (rhGAA) In Vitro and Its Presence in Serum In Vivo

by Allen K. Murray

Biomolecules 2020, 10(12), 1613; https://doi.org/10.3390/biom10121613 - 29 Nov 2020

Cited by 3 | Viewed by 2765

Abstract

In studies on the degradation of glycogen by rhGAA, a glycosylated protein core material was found which consists of about 5–6% of the total starting glycogen. There was an additional 25% of the glycogen unaccounted for based on glucose released. After incubation of [...] Read more.

In studies on the degradation of glycogen by rhGAA, a glycosylated protein core material was found which consists of about 5–6% of the total starting glycogen. There was an additional 25% of the glycogen unaccounted for based on glucose released. After incubation of glycogen with rhGAA until no more glucose was released, no other carbohydrate was detected on HPAEC-PAD. Several oligosaccharides are then detectable if the medium is first boiled in 0.1 N HCl or incubated with trypsin. It is present in serum either in an HCl extract or in a trypsin digest. The characteristics of the in vivo serum material are identical to the material in the in vitro incubation medium. One oligosaccharide cannot be further degraded by rhGAA, from the incubation medium as well as from serum co-elute on HPAEC-PAD. Several masked oligosaccharides in serum contain m-inositol, e-inositol, and sorbitol as the major carbohydrates. The presence of this glycosylated protein in serum is a fraction of glycogen that is degraded outside the lysosome and the cell. The glycosylated protein in the serum is not present in the serum of Pompe mice not on ERT, but it is present in the serum of Pompe disease patients who are on ERT, so it is a biomarker of GAA degradation of lysosomal glycogen. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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20 pages, 4734 KiB

Open AccessFeature PaperArticle

Rapid Clathrin-Mediated Uptake of Recombinant α-Gal-A to Lysosome Activates Autophagy

by Margarita M. Ivanova, Julia Dao, Neil Kasaci, Benjamin Adewale, Jacqueline Fikry and Ozlem Goker-Alpan

Biomolecules 2020, 10(6), 837; https://doi.org/10.3390/biom10060837 - 30 May 2020

Cited by 8 | Viewed by 4782

Abstract

Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A (rh-α-Gal A) is the standard treatment for Fabry disease (FD). ERT has shown a significant impact on patients; however, there is still morbidity and mortality in FD, resulting in progressive cardiac, renal, and cerebrovascular pathology. [...] Read more.

Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A (rh-α-Gal A) is the standard treatment for Fabry disease (FD). ERT has shown a significant impact on patients; however, there is still morbidity and mortality in FD, resulting in progressive cardiac, renal, and cerebrovascular pathology. The main pathway for delivery of rh-α-Gal A to lysosome is cation-independent mannose-6-phosphate receptor (CI-M6PR) endocytosis, also known as insulin-like growth factor 2 receptor (IGF2R) endocytosis. This study aims to investigate the mechanisms of uptake of rh-α-Gal-A in different cell types, with the exploration of clathrin-dependent and caveolin assisted receptor-mediated endocytosis and the dynamics of autophagy-lysosomal functions. rh-α-Gal-A uptake was evaluated in primary fibroblasts, urine originated kidney epithelial cells, and peripheral blood mononuclear cells derived from Fabry patients and healthy controls, and in cell lines HEK293, HTP1, and HUVEC. Uptake of rh-α-Gal-A was more efficient in the cells with the lowest endogenous enzyme activity. Chloroquine and monensin significantly blocked the uptake of rh-α-Gal-A, indicating that the clathrin-mediated endocytosis is involved in recombinant enzyme delivery. Alternative caveolae-mediated endocytosis coexists with clathrin-mediated endocytosis. However, clathrin-dependent endocytosis is a dominant mechanism for enzyme uptake in all cell lines. These results show that the uptake of rh-α-Gal-A occurs rapidly and activates the autophagy-lysosomal pathway. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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19 pages, 2570 KiB

Open AccessArticle

Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells

by Jarrod W. Barnes, Megan Aarnio-Peterson, Joy Norris, Mark Haskins, Heather Flanagan-Steet and Richard Steet

Biomolecules 2020, 10(5), 670; https://doi.org/10.3390/biom10050670 - 26 Apr 2020

Cited by 5 | Viewed by 3768

Abstract

Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth factor signaling has been identified as a contributor to the phenotypes associated with ML-II and other lysosomal disorders but an understanding of [...] Read more.

Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth factor signaling has been identified as a contributor to the phenotypes associated with ML-II and other lysosomal disorders but an understanding of how these signaling pathways are affected is still emerging. Here, we investigated transforming growth factor beta 1 (TGFβ1) signaling in the context of ML-II patient fibroblasts, observing decreased TGFβ1 signaling that was accompanied by impaired TGFβ1-dependent wound closure. We found increased intracellular latent TGFβ1 complexes, caused by reduced secretion and stable localization in detergent-resistant lysosomes. Sortilin, a sorting receptor for hydrolases and TGFβ-related cytokines, was upregulated in ML-II fibroblasts as well as GNPTAB-null HeLa cells, suggesting a mechanism for inappropriate lysosomal targeting of TGFβ. Co-expression of sortilin and TGFβ in HeLa cells resulted in reduced TGFβ1 secretion. Elevated sortilin levels correlated with normal levels of cathepsin D in ML-II cells, consistent with a compensatory role for this receptor in lysosomal hydrolase targeting. Collectively, these data support a model whereby sortilin upregulation in cells with lysosomal storage maintains hydrolase sorting but suppresses TGFβ1 secretion through increased lysosomal delivery. These findings highlight an unexpected link between impaired lysosomal sorting and altered growth factor bioavailability. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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12 pages, 1621 KiB

Open AccessArticle

Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease

by Renuka P. Limgala and Ozlem Goker-Alpan

Biomolecules 2020, 10(4), 526; https://doi.org/10.3390/biom10040526 - 31 Mar 2020

Cited by 12 | Viewed by 4226

Abstract

Gaucher disease (GD) is caused by mutations in the GBA gene, leading to deficient activity of the lysosomal enzyme glucocerebrosidase. Among all the symptoms across various organ systems, bone disease is a major concern as it causes high morbidity and reduces quality of [...] Read more.

Gaucher disease (GD) is caused by mutations in the GBA gene, leading to deficient activity of the lysosomal enzyme glucocerebrosidase. Among all the symptoms across various organ systems, bone disease is a major concern as it causes high morbidity and reduces quality of life. Enzyme replacement therapy (ERT) is the most accepted treatment; however, there are still unmet needs. As an alternative, substrate reduction therapy (SRT) was developed using glucosylceramide synthase inhibitors. In the current study, the effects of ERT vs. SRT were compared, particularly the immunological and bone remodeling aspects. GD subjects were divided into three cohorts based on their treatment at initial visit: ERT, SRT, and untreated (UT). Immunophenotyping showed no significant immune cell alterations between the cohorts. Expression of RANK/RANKL/Osteoprotegerin pathway components on immune cells and the secreted markers of bone turnover were analyzed. In the ERT cohort, no significant changes were observed in RANK, RANKL or serum biomarkers. RANKL on T lymphocytes, Osteopontin and MIP-1β decreased with SRT treatment indicating probable reduction in osteoclast activity. Other secreted factors, Osteocalcin and RANKL/Osteoprotegerin did not change with the treatment status. Insights from the study highlight personalized differences between subjects and possible use of RANK pathway components as markers for bone disease progression. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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24 pages, 5102 KiB

Open AccessArticle

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

by Valeria De Pasquale, Michele Costanzo, Rosa Anna Siciliano, Maria Fiorella Mazzeo, Valeria Pistorio, Laura Bianchi, Emanuela Marchese, Margherita Ruoppolo, Luigi Michele Pavone and Marianna Caterino

Biomolecules 2020, 10(3), 355; https://doi.org/10.3390/biom10030355 - 26 Feb 2020

Cited by 31 | Viewed by 4072

Abstract

Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was [...] Read more.

Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice to identify altered neuropathological pathways of MPS IIIB. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses allowed to identify three major clusters of the differentially abundant proteins: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The proteome profile of NAGLU^−/− mouse brain could pave the way for further studies aimed at identifying novel therapeutic targets for the MPS IIIB. Data are available via ProteomeXchange with the identifier PXD017363. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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Review

Jump to: Editorial, Research

23 pages, 910 KiB

Open AccessReview

Acid Ceramidase Deficiency: Bridging Gaps between Clinical Presentation, Mouse Models, and Future Therapeutic Interventions

by Annie Kleynerman, Jitka Rybova, Mary L. Faber, William M. McKillop, Thierry Levade and Jeffrey A. Medin

Biomolecules 2023, 13(2), 274; https://doi.org/10.3390/biom13020274 - 1 Feb 2023

Cited by 6 | Viewed by 4153

Abstract

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare, autosomal-recessive, acid ceramidase (ACDase) deficiency disorders caused by ASAH1 gene mutations. Currently, 73 different mutations in the ASAH1 gene have been described in humans. These mutations lead to reduced [...] Read more.

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare, autosomal-recessive, acid ceramidase (ACDase) deficiency disorders caused by ASAH1 gene mutations. Currently, 73 different mutations in the ASAH1 gene have been described in humans. These mutations lead to reduced ACDase activity and ceramide (Cer) accumulation in many tissues. Presenting as divergent clinical phenotypes, the symptoms of FD vary depending on central nervous system (CNS) involvement and severity. Classic signs of FD include, but are not limited to, a hoarse voice, distended joints, and lipogranulomas found subcutaneously and in other tissues. Patients with SMA-PME lack the most prominent clinical signs seen in FD. Instead, they demonstrate muscle weakness, tremors, and myoclonic epilepsy. Several ACDase-deficient mouse models have been developed to help elucidate the complex consequences of Cer accumulation. In this review, we compare clinical reports on FD patients and experimental descriptions of ACDase-deficient mouse models. We also discuss clinical presentations, potential therapeutic strategies, and future directions for the study of FD and SMA-PME. Full article

(This article belongs to the Special Issue Upscaling the Basic Knowledge of Lysosomal Storage Disorders: Novel Insights into the Pathogenic Mechanisms and Emerging Therapeutic Approaches)

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8 pages, 597 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction

by Chase Chen, Ellen Sidransky and Yu Chen

Biomolecules 2022, 12(5), 616; https://doi.org/10.3390/biom12050616 - 21 Apr 2022

Cited by 7 | Viewed by 6794

Abstract

Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage [...] Read more.

Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. New technological advances have significantly increased our ability to rapidly isolate lysosomes from cells in recent years. The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. Multiple studies using the Lyso-IP approach have revealed novel insights into the pathogenic mechanisms of lysosomal disorders, including Niemann-Pick type C disease, showing the immense potential for this technique. Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes. Full article

(This article belongs to the Special Issue Upscaling the Basic Knowledge of Lysosomal Storage Disorders: Novel Insights into the Pathogenic Mechanisms and Emerging Therapeutic Approaches)

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41 pages, 1105 KiB

Open AccessFeature PaperReview

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development

by Giulia Massaro, Amy F. Geard, Wenfei Liu, Oliver Coombe-Tennant, Simon N. Waddington, Julien Baruteau, Paul Gissen and Ahad A. Rahim

Biomolecules 2021, 11(4), 611; https://doi.org/10.3390/biom11040611 - 20 Apr 2021

Cited by 35 | Viewed by 8015

Abstract

Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy [...] Read more.

Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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20 pages, 2738 KiB

Open AccessReview

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

by Ken Kok, Kimberley C. Zwiers, Rolf G. Boot, Hermen S. Overkleeft, Johannes M. F. G. Aerts and Marta Artola

Biomolecules 2021, 11(2), 271; https://doi.org/10.3390/biom11020271 - 12 Feb 2021

Cited by 61 | Viewed by 12407

Abstract

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to [...] Read more.

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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13 pages, 637 KiB

Open AccessFeature PaperReview

Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison?

by Rosa Manzoli, Lorenzo Badenetti, Michela Rubin and Enrico Moro

Biomolecules 2021, 11(2), 191; https://doi.org/10.3390/biom11020191 - 29 Jan 2021

Cited by 9 | Viewed by 4464

Abstract

Axonal trajectories and neural circuit activities strongly rely on a complex system of molecular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely understood intracellular mechanisms, that in [...] Read more.

Axonal trajectories and neural circuit activities strongly rely on a complex system of molecular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely understood intracellular mechanisms, that in part rely on endocytic and autophagic cascades. Based on their pivotal role in both pathways, lysosomes are emerging as a key hub in the sophisticated regulation of axonal guidance cue delivery, localization, and function. In this review, we will attempt to collect some of the most relevant research on the tight connection between lysosomal function and axon guidance regulation, providing some proof of concepts that may be helpful to understanding the relation between lysosomal storage disorders and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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24 pages, 449 KiB

Open AccessReview

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement

by Christiane S. Hampe, Jacob Wesley, Troy C. Lund, Paul J. Orchard, Lynda E. Polgreen, Julie B. Eisengart, Linda K. McLoon, Sebahattin Cureoglu, Patricia Schachern and R. Scott McIvor

Biomolecules 2021, 11(2), 189; https://doi.org/10.3390/biom11020189 - 29 Jan 2021

Cited by 45 | Viewed by 7737

Abstract

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded [...] Read more.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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19 pages, 588 KiB

Open AccessReview

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

by Naresh K. Meena and Nina Raben

Biomolecules 2020, 10(9), 1339; https://doi.org/10.3390/biom10091339 - 18 Sep 2020

Cited by 69 | Viewed by 15564

Abstract

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase [...] Read more.

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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24 pages, 363 KiB

Open AccessReview

Precision Medicine for Lysosomal Disorders

by Filippo Pinto e Vairo, Diana Rojas Málaga, Francyne Kubaski, Carolina Fischinger Moura de Souza, Fabiano de Oliveira Poswar, Guilherme Baldo and Roberto Giugliani

Biomolecules 2020, 10(8), 1110; https://doi.org/10.3390/biom10081110 - 26 Jul 2020

Cited by 10 | Viewed by 3969

Abstract

Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions [...] Read more.

Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primary lysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzyme activators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and the phenotype of the affected individual depends on the type of substrate and where it accumulates, which may be impacted by the type of genetic change and residual enzymatic activity. LDs are individually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapies are already available for several LDs, and many more are in development. Early identification may enable disease course prediction and a specific intervention, which is very important for clinical outcome. Driven by advances in omics technology, PM aims to provide the most appropriate management for each patient based on the disease susceptibility or treatment response predictions for specific subgroups. In this review, we focused on the emerging diagnostic technologies that may help to optimize the management of each LD patient and the therapeutic options available, as well as in clinical developments that enable customized approaches to be selected for each subject, according to the principles of PM. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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