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Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical...
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Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (20 January 2025) | Viewed by 7972

Special Issue Editor

Dr. Margarita Ivanova

E-Mail Website
Guest Editor
Lysosomal and Rare Disorders Research and Treatment Center, Faitfax, VA 22030, USA
Interests: lysosomal storage disorders; autophagy–lysosomal pathway; sphingolipids metabolism; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lysosomal diseases (LD) comprise more than 50 inherited disorders caused by mutations in the genes encoding lysosomal enzymes or cofactors related to substrate degradation pathways.

The research exploring the lysosome's metabolic functions has led to our understanding the roles of cell signaling, metabolite sensing, and the pathways involved in cell death and survival that significantly contribute to disease pathology and progression. New cellular and molecular techniques powered by "omics" are leading to the development of disease-specific biomarkers for clinical use and advanced therapies for LDs, such as gene therapy, small-molecule/nanomedicine approaches, RNA silencing, and genome editing. These innovative approaches have the potential to revolutionize therapies by targeting the underlying genetic and molecular mechanisms of the diseases. Moreover, the advent of novel developments and emerging technologies makes it imperative to address the role of downstream pathways in LDs to pursue precision or individualized medicine for patients with LDs.

Therefore, this Special Issue will focus on the latest advances, technological breakthroughs, and innovative diagnostics tools and therapies that are changing the LD landscape. We invite researchers to expand upon the discussion regarding the role of cell signaling, metabolite regulation, and inflammatory and other pathways to gain a better understanding of the disease process. 

 We look forward to your contributions.

Dr. Margarita Ivanova
Guest Editor

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Keywords

  • lysosomal storage diseases
  • omics
  • autophagy
  • mitochondria
  • advance therapy
  • biomarkers
  • precision medicine
  • genetic diseases
  • epigenetics
  • neurodegeneration

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Published Papers (4 papers)

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Research

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20 pages, 4395 KiB  
Article
Sex Differences in Circulating Inflammatory, Immune, and Tissue Growth Markers Associated with Fabry Disease-Related Cardiomyopathy
by Margarita M. Ivanova, Julia Dao, Andrew Friedman, Neil Kasaci and Ozlem Goker-Alpan
Cells 2025, 14(5), 322; https://doi.org/10.3390/cells14050322 - 20 Feb 2025
Viewed by 1197
Abstract
Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response [...] Read more.
Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response to Gb3/lyso-Gb-3 accumulation is one of the suggested pathogenic mechanisms in FD cardiomyopathy when the secretion of inflammatory and transforming growth factors with infiltration of lymphocytes and macrophages into tissue promotes cardiofibrosis. This study aims to evaluate inflammation-driving cytokines and cardio-hypertrophic remodeling biomarkers contributing to sex-specific HCM progression. Biomarkers were studied in 20 healthy subjects and 45 FD patients. IL-2, IL-10, TNF-α, and IFN-γ were elevated in all patients, while IL-1α, MCP-1, and TNFR2 showed sex-specific differences. The increased cytokines were associated with the NF-kB pathway in FD males with HCM, revealing a correlation between MCP-1, IFN-γ, VEGF, GM-CSF, IL-10, and IL-2. In female patients, the impaired TNFα/TNFR2/TGFβ cluster with correlations to MCP-1, VEGF, GM-CSF, and IL-1α was observed. The activation of cytokines and the NF-kB pathway indicates significant inflammation during HCM remodeling in FD males. The TNFα/TNFR2/TGFβ signaling cluster may explain early fibrosis in females with FD cardiomyopathy. Sex-specific inflammatory responses in FD influence the severity and progression of HCM. Full article
(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)
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23 pages, 2667 KiB  
Article
Functional Analysis of Human GBA1 Missense Mutations in Drosophila: Insights into Gaucher Disease Pathogenesis and Phenotypic Consequences
by Aparna Kuppuramalingam, Or Cabasso and Mia Horowitz
Cells 2024, 13(19), 1619; https://doi.org/10.3390/cells13191619 - 27 Sep 2024
Cited by 1 | Viewed by 1637
Abstract
The human GBA1 gene encodes lysosomal acid β-glucocerebrosidase, whose activity is deficient in Gaucher disease (GD). In Drosophila, there are two GBA1 orthologs, Gba1a and Gba1b, and Gba1b is the bona fide GCase encoding gene. Several fly lines with different deletions [...] Read more.
The human GBA1 gene encodes lysosomal acid β-glucocerebrosidase, whose activity is deficient in Gaucher disease (GD). In Drosophila, there are two GBA1 orthologs, Gba1a and Gba1b, and Gba1b is the bona fide GCase encoding gene. Several fly lines with different deletions in the Gba1b were studied in the past. However, since most GD-associated GBA1 mutations are point mutations, we created missense mutations homologous to the two most common GD mutations: the mild N370S mutation (D415S in Drosophila) and the severe L444P mutation (L494P in Drosophila), using the CRISPR-Cas9 technology. Flies homozygous for the D415S mutation (dubbed D370S hereafter) presented low GCase activity and substrate accumulation, which led to lysosomal defects, activation of the Unfolded Protein Response (UPR), inflammation/neuroinflammation, and neurodegeneration along with earlier death compared to control flies. Surprisingly, the L494P (called L444P hereafter) flies presented higher GCase activity with fewer lysosomal defects and milder disease in comparison to that presented by the D370S homozygous flies. Treatment with ambroxol had a limited effect on all homozygous fly lines tested. Overall, our results underscore the differences between the fly and human GCase enzymes, as evidenced by the distinct phenotypic outcomes of mutations in flies compared to those observed in human GD patients. Full article
(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)
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21 pages, 4624 KiB  
Article
Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC
by Xuefang Pan, Antoine Caillon, Shuxian Fan, Shaukat Khan, Shunji Tomatsu and Alexey V. Pshezhetsky
Cells 2024, 13(10), 877; https://doi.org/10.3390/cells13100877 - 20 May 2024
Cited by 3 | Viewed by 1725
Abstract
Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or [...] Read more.
Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or their cross-correction, which limits development of therapies based on enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied using behavior test battery, starting from the age of 6 months. At the age of ~8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage, and other biomarkers of the disease. We found that the treatment corrected several behavior deficits including hyperactivity and reduction in socialization, but not memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1β, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with cells from a normal healthy donor. They also suggest that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology. Full article
(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)
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Review

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18 pages, 1470 KiB  
Review
Unveiling the Roles of Cysteine Proteinases F and W: From Structure to Pathological Implications and Therapeutic Targets
by Kristina Zdravkova, Olja Mijanovic, Ana Brankovic, Polina M. Ilicheva, Aleksandra Jakovleva, Jelena Karanovic, Milena Pualic, Dusan Pualic, Aleksandr A. Rubel, Lyudmila V. Savvateeva, Alessandro Parodi and Andrey A. Zamyatnin, Jr.
Cells 2024, 13(11), 917; https://doi.org/10.3390/cells13110917 - 25 May 2024
Cited by 1 | Viewed by 2868
Abstract
Cysteine cathepsins F and W are members of the papain-like cysteine protease family, which have distinct structural features and functional roles in various physiological and pathological processes. This review provides a comprehensive overview of the current understanding of the structure, biological functions, and [...] Read more.
Cysteine cathepsins F and W are members of the papain-like cysteine protease family, which have distinct structural features and functional roles in various physiological and pathological processes. This review provides a comprehensive overview of the current understanding of the structure, biological functions, and pathological implications of cathepsins F and W. Beginning with an introduction to these proteases, we delve into their structural characteristics and elucidate their unique features that dictate their enzymatic activities and substrate specificity. We also explore the intricate involvement of cathepsins F and W in malignancies, highlighting their role as potential biomarkers and therapeutic targets in cancer progression. Furthermore, we discuss the emerging roles of these enzymes in immune response modulation and neurological disorders, shedding light on their implications in autoimmune and neurodegenerative diseases. Finally, we review the landscape of inhibitors targeting these proteases, highlighting their therapeutic potential and challenges in clinical translation. This review brings together the diverse facets of cysteine cathepsins F and W, providing insights into their roles in health and disease and guiding future investigations for therapeutic advances. Full article
(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)
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