Special Issue "Molecular Mechanisms in Lysosomal Storage Diseases: From Pathogenesis to Therapeutic Strategies"

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 9377

Special Issue Editors

Dr. Luigi Michele Pavone
E-Mail Website
Guest Editor
Department Molecular Medicines and Medical Biotechnology, University of Naples Federico II, Via S Pansini 5, I-80131 Naples, Italy.
Interests: lysosomal storage diseases; mucopolysaccharidoses; heparan sulfate proteoglycans; growth factors; cytokine; cathepsin proteases; metabolism; autophagy; cell signaling; metabolic diseases
Dr. Valeria De Pasquale
E-Mail Website
Guest Editor
Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Unina, Italy
Interests: lysosomal storage diseases; mucopolysaccharidoses; heparan sulfate proteoglycans; growth factors; cytokine; cathepsin proteases; metabolism; autophagy; cell signalling; metabolic diseases

Special Issue Information

Dear Colleagues,

Lysosomal storage disorders (LSDs) are a group of about 50 inherited metabolic diseases that are characterized by the accumulation of undegraded products within the lysosomes, resulting in the formation of large intracellular vacuoles. Although individually rare, the lysosomal storage disorders as a group have a frequency of about 1/5000 live births, making this disease group a major challenge for the healthcare system.

Over the last two decades, there has been a huge expansion of investigations in the field of LSDs, which has greatly increased our understanding of their pathogenic mechanisms. These studies have disclosed the important role of the altered autophagy flux and mitochondrial function, which along with the stimulation of inflammatory responses appear to represent a common feature of many LSDs. In addition, the interplay between the accumulation/mislocalization of substrates and the alteration of many signaling pathways is also gaining attention in the context of LSDs. Despite that, current therapeutic options, mostly consisting of enzyme replacement therapies, are only available for a few LSDs. These therapies show poor efficacy to rescue the neurological manifestations. Hence, the identification and validation of novel therapeutic approaches exhibiting improved efficacy and the ability to target the central nervous system represent an absolute requirement.

This Special Issue is devoted to publishing results on any features of LSDs, including basic research on molecular mechanisms of LSDs, translational studies on novel therapies, and clinical investigations. Review articles on all these aspects are also welcome, as well as any study including the relationship between LSDs and more common neurodegenerative diseases such as Alzheimer’s or Parkinson’s. This Special Issue will provide a comprehensive view of the molecular aspects of various LSDs. We aim to provide a comprehensive update on LSDs and their pathomechanisms and therapeutic strategies. It comprehensively covers many areas in the LSDs field and could be of interest to a broad range of readers including physicians, scientists, students, pharmaceutical companies, and LSDs communities.

Dr. Luigi Michele Pavone
Dr. Valeria De Pasquale
Guest Editors

Manuscript Submission Information

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Keywords

  • lysosomal storage disorders
  • novel therapies for genetic diseases
  • molecular diagnosis
  • biomarkers
  • substrate storage
  • autophagy
  • cell signaling
  • molecular mechanisms of genetic disorders
  • neurodegeneration
  • metabolic diseases

Published Papers (8 papers)

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Editorial

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Editorial
Molecular Mechanisms in Lysosomal Storage Diseases: From Pathogenesis to Therapeutic Strategies
Biomedicines 2022, 10(4), 922; https://doi.org/10.3390/biomedicines10040922 - 17 Apr 2022
Viewed by 457
Abstract
Lysosomal storage diseases (LSDs) are a group of metabolic diseases caused by inborn mutations of lysosomal enzymes, which lead to lysosome substrate accumulation in various cell types [...] Full article

Research

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Article
Storage of Mutant Human SOD1 in Non-Neural Cells from the Type-1 Amyotrophic Lateral Sclerosis ratG93A Model Correlated with the Lysosomes’ Dysfunction
Biomedicines 2021, 9(9), 1080; https://doi.org/10.3390/biomedicines9091080 - 24 Aug 2021
Cited by 2 | Viewed by 863
Abstract
Herein, we explored the impact of the lysosome dysfunction during the progression of Amyotrophic Lateral Sclerosis type-1 (ALS1). We conducted the study in non-neural cells, primary fibroblasts (rFFFs), and bone marrow-mesenchymal stem cells (rBM-MSCs), isolated from the animal model ratG93A for ALS1 [...] Read more.
Herein, we explored the impact of the lysosome dysfunction during the progression of Amyotrophic Lateral Sclerosis type-1 (ALS1). We conducted the study in non-neural cells, primary fibroblasts (rFFFs), and bone marrow-mesenchymal stem cells (rBM-MSCs), isolated from the animal model ratG93A for ALS1 at two stages of the disease: Pre-symptomatic-stage (ALS1-PreS) and Terminal-stage (ALS1-EndS). We documented the storage of human mutant Superoxide Dismutase 1, SOD1G93A (SOD1*) in the lysosomes of ALS1-rFFFs and ALS1-rBM-MSCs and demonstrated the hallmarks of the disease in non-neural cells as in ratG93A-ALS1-tissues. We showed that the SOD1* storage is associated with the altered glycohydrolases and proteases levels in tissues and both cell types from ALS1-PreS to ALS1-EndS. Only in ALS1-rFFFs, the lysosomes lost homeostasis, enlarge drastically, and contribute to the cell metabolic damage. Contrariwise, in ALS1-rBM-MSCs, we found a negligible metabolic dysfunction, which makes these cells’ status similar to WT. We addressed this phenomenon to a safety mechanism perhaps associated with an enhanced lysosomal autophagic activity in ALS1-rBM-MSCs compared to ALS1-rFFFs, in which the lysosomal level of LC3-II/LC3I was comparable to that of WT-rFFFs. We suggested that the autophagic machinery could balance the storage of SOD1* aggregates and the lysosomal enzyme dysfunction even in ALS1-EndS-stem cells. Full article
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Article
Murine Models of Lysosomal Storage Diseases Exhibit Differences in Brain Protein Aggregation and Neuroinflammation
Biomedicines 2021, 9(5), 446; https://doi.org/10.3390/biomedicines9050446 - 21 Apr 2021
Cited by 3 | Viewed by 1210
Abstract
Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson’s disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of synucleinopathies. We obtained brain tissue from symptomatic mouse models of Gaucher, Fabry, Sandhoff, Niemann–Pick [...] Read more.
Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson’s disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of synucleinopathies. We obtained brain tissue from symptomatic mouse models of Gaucher, Fabry, Sandhoff, Niemann–Pick A (NPA), Hurler, Pompe and Niemann–Pick C (NPC) diseases and assessed for the presence of Lewy body-like pathology (proteinase K-resistant α-synuclein and tau aggregates) and neuroinflammation (microglial Iba1 and astrocytic GFAP) by immunofluorescence. All seven LSD models exhibited evidence of proteinopathy and/or inflammation in the central nervous system (CNS). However, these phenotypes were divergent. Gaucher and Fabry mouse models displayed proteinase K-resistant α-synuclein and tau aggregates but no neuroinflammation; whereas Sandhoff, NPA and NPC showed marked neuroinflammation and no overt proteinopathy. Pompe disease animals uniquely displayed widespread distribution of tau aggregates accompanied by moderate microglial activation. Hurler mice also demonstrated proteinopathy and microglial activation. The present study demonstrated additional links between LSDs and pathogenic phenotypes that are hallmarks of synucleinopathies. The data suggest that lysosomal dysregulation can contribute to brain region-specific protein aggregation and induce widespread neuroinflammation in the brain. However, only a few LSD models examined exhibited phenotypes consistent with synucleinopathies. While no model can recapitulate the complexity of PD, they can enable the study of specific pathways and mechanisms contributing to disease pathophysiology. The present study provides evidence that there are existing, previously unutilized mouse models that can be employed to study pathogenic mechanisms and gain insights into potential PD subtypes, helping to determine if they are amenable to pathway-specific therapeutic interventions. Full article
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Article
Artificially Induced Pluripotent Stem Cell-Derived Whole-Brain Organoid for Modelling the Pathophysiology of Metachromatic Leukodystrophy and Drug Repurposing
Biomedicines 2021, 9(4), 440; https://doi.org/10.3390/biomedicines9040440 - 20 Apr 2021
Cited by 1 | Viewed by 829
Abstract
Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments [...] Read more.
Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments for MLD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of MLD pathogenesis. However, developing brain organoid models is expensive, time consuming and may not accurately reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids could overcome the current limitations. Artificially induced whole-brain organoids (aiWBO) have the potential to greatly expand our ability to model MLD and guide future wet lab research. In this study, we have upgraded and validated our artificially induced whole-brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.2). Using this upgraded NEUBorg, we have generated aiWBO simulations of MLD and provided a novel approach to evaluate factors associated with MLD pathogenesis, disease progression and new potential therapeutic options. Full article
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Article
Screening for Fabry Disease in Kidney Transplant Recipients: Experience of a Multidisciplinary Team
Biomedicines 2020, 8(10), 396; https://doi.org/10.3390/biomedicines8100396 - 07 Oct 2020
Cited by 8 | Viewed by 1242
Abstract
Fabry disease (FD) is a rare cause of end-stage renal disease requiring kidney transplantation. Data on the incidence of unrecognized FD in kidney transplant recipients are scarce and probably underestimated. This study evaluated the incidence of FD in a population of kidney recipients, [...] Read more.
Fabry disease (FD) is a rare cause of end-stage renal disease requiring kidney transplantation. Data on the incidence of unrecognized FD in kidney transplant recipients are scarce and probably underestimated. This study evaluated the incidence of FD in a population of kidney recipients, with a particular focus of the multidisciplinary approach for an early clinical assessment and therapeutic approach. Two hundred sixty-five kidney transplant recipients were screened with a genetic analysis for α-galactosidase A (GLA) mutation, with measurement of α-Gal A enzyme activity and Lyso Gb3 levels. Screening was also extended to relatives of affected patients. Seven patients (2.6%) had a GLA mutation. Two patients had a classic form of FD with Fabry nephropathy. Among the relatives, 15 subjects had a GLA mutation, and two had a Fabry nephropathy. The clinical and diagnostic assessment was completed after a median of 3.2 months, and mean time from diagnosis to treatment was 4.6 months. This study reported a high incidence of unrecognized GLA mutations in kidney transplant recipients. Evaluation and management by a multidisciplinary team allowed for an early diagnosis and treatment, and this would result in a delay in the progression of the disease and, finally, in better long-term outcomes. Full article

Review

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Review
Surgical Management of Valvular Heart Disease in Mucopolysaccharidoses: A Review of Literature
Biomedicines 2022, 10(2), 375; https://doi.org/10.3390/biomedicines10020375 - 04 Feb 2022
Cited by 2 | Viewed by 546
Abstract
Mucopolysaccharidoses are extremely rare diseases that are frequently presenting with structural heart problems of the aortic and mitral valve in combination with myocardial dysfunction. In a substantial proportion, this leads to heart failure and is a leading cause of death in these patients. [...] Read more.
Mucopolysaccharidoses are extremely rare diseases that are frequently presenting with structural heart problems of the aortic and mitral valve in combination with myocardial dysfunction. In a substantial proportion, this leads to heart failure and is a leading cause of death in these patients. As this glycosaminoglycan degradation defect is associated with other conditions strongly influencing the perioperative risk and choice of surgical technique, multidisciplinary planning is crucial to improve short- and long-term outcomes. The extensive variance in clinical presentation between different impaired enzymes, and further within subgroups, calls for personalised treatment plans. Enzyme replacement therapies and bone marrow transplantation carry great potential as they may significantly abrogate the progress of the disease and as such reduce the clinical burden and improve life expectancy. Nevertheless, structural heart interventions may be required. We reviewed the existing literature of the less than 50 published cases regarding surgical management, technique, and choice of prostheses. Although improvement in therapy has shown promising results in protecting valvar tissue when initiated in infancy, concerns regarding stability of this effect and durability of biological prostheses remain. Full article
Review
Exploiting the Potential of Drosophila Models in Lysosomal Storage Disorders: Pathological Mechanisms and Drug Discovery
Biomedicines 2021, 9(3), 268; https://doi.org/10.3390/biomedicines9030268 - 07 Mar 2021
Cited by 6 | Viewed by 1376
Abstract
Lysosomal storage disorders (LSDs) represent a complex and heterogeneous group of rare genetic diseases due to mutations in genes coding for lysosomal enzymes, membrane proteins or transporters. This leads to the accumulation of undegraded materials within lysosomes and a broad range of severe [...] Read more.
Lysosomal storage disorders (LSDs) represent a complex and heterogeneous group of rare genetic diseases due to mutations in genes coding for lysosomal enzymes, membrane proteins or transporters. This leads to the accumulation of undegraded materials within lysosomes and a broad range of severe clinical features, often including the impairment of central nervous system (CNS). When available, enzyme replacement therapy slows the disease progression although it is not curative; also, most recombinant enzymes cannot cross the blood-brain barrier, leaving the CNS untreated. The inefficient degradative capability of the lysosomes has a negative impact on the flux through the endolysosomal and autophagic pathways; therefore, dysregulation of these pathways is increasingly emerging as a relevant disease mechanism in LSDs. In the last twenty years, different LSD Drosophila models have been generated, mainly for diseases presenting with neurological involvement. The fruit fly provides a large selection of tools to investigate lysosomes, autophagy and endocytic pathways in vivo, as well as to analyse neuronal and glial cells. The possibility to use Drosophila in drug repurposing and discovery makes it an attractive model for LSDs lacking effective therapies. Here, ee describe the major cellular pathways implicated in LSDs pathogenesis, the approaches available for their study and the Drosophila models developed for these diseases. Finally, we highlight a possible use of LSDs Drosophila models for drug screening studies. Full article
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Review
Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation
Biomedicines 2020, 8(8), 272; https://doi.org/10.3390/biomedicines8080272 - 04 Aug 2020
Cited by 10 | Viewed by 1850
Abstract
In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. [...] Read more.
In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases. Full article
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