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Cells
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Cellular and Molecular Mechanisms of Lysosomal Storage Disorders
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Cellular and Molecular Mechanisms of Lysosomal Storage Disorders

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

Deadline for manuscript submissions: closed (15 April 2025) | Viewed by 7312

Special Issue Editor

Prof. Dr. Ritva Tikkanen

E-Mail Website
Guest Editor
Institute of Biochemistry, Medical Faculty, Justus-Liebig University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany
Interests: lysosomal storage disorders; vesicular trafficking; endosomal sorting; lysosome biogenesis; mitochondrial diseases; autoimmune disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lysosomal storage disorders (LSDs) are rare, monogenic diseases that are characterized by aberrant lysosomes with storage material. These diseases often manifest as neurodegeneration and are associated with a reduced life span. Many of the LSDs result from a deficiency of a single enzyme, whereas others are caused by mutations in non-enzymatic proteins. The molecular mechanisms and cellular pathology of these diseases have been subject to intensive research for decades, but only few therapy options for these diseases are available. However, ever more preclinical studies on novel therapies such as gene therapy, chaperone therapy and enzyme replacement therapy are emerging in the last few years.

The purpose of this Special Issue is to summarize our current understanding about the disease pathogenesis and molecular mechanisms of LSDs, and to explore therapeutic strategies that could be used in LSDs. We also welcome manuscripts addressing the involvement of various cellular pathways such as autophagy, neuroinflammation, endosomal dysfunction and signaling pathways in the pathogenesis of LSDs. Novel concepts such as the common features of LSDs and other neurodegenerative diseases such as Alzheimer’s or Parkinson’s are also subjects of interest for this Special Issue. We encourage the submission of comprehensive review articles and original research papers. Our aim is to provide a comprehensive update on LSDs, their pathomechanisms and therapy options.

Prof. Dr. Ritva Tikkanen
Guest Editor

Manuscript Submission Information

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Keywords

  • lysosomes
  • lysosomal storage disorders
  • enzyme replacement
  • gene therapy
  • substrate reduction
  • pharmacological chaperones
  • autophagy
  • endosomal dysfunction

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Published Papers (4 papers)

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Research

20 pages, 2703 KB  
Article
Deciphering α-L-Fucosidase Activity Contribution in Human and Mouse: Tissue α-L-Fucosidase FUCA1 Meets Plasma α-L-Fucosidase FUCA2
by Hannah Bäumges, Svenja Jelinek, Heike Lange, Sandra Markmann, Emanuela Capriotti, Jan Anwar Häusser, Mai-Britt Ilse, Thomas Braulke and Torben Lübke
Cells 2025, 14(17), 1355; https://doi.org/10.3390/cells14171355 - 30 Aug 2025
Viewed by 394
Abstract
Fucose-containing glycoproteins and glycolipids broadly occur in humans as well as in many other species and are essential for a wide range of physiological processes, such as cell adhesion, fertilization, and tumor development. In humans, the cellular degradation of various fucosylated glycoconjugates depends [...] Read more.
Fucose-containing glycoproteins and glycolipids broadly occur in humans as well as in many other species and are essential for a wide range of physiological processes, such as cell adhesion, fertilization, and tumor development. In humans, the cellular degradation of various fucosylated glycoconjugates depends on the FUCA1-encoded lysosomal tissue α-L-fucosidase (FUCA1). The crucial role of FUCA1 is reflected by the severe lysosomal storage disease fucosidosis, which causes a massive accumulation of fucosylated glycans, glycolipids, and α(1,6)-fucosylated glycoasparagines. Therefore, it is reasonable to assume that FUCA1 is predominantly responsible for the degradation of fucosylated glycoconjugates, although a second, functionally uncharacterized α-L-fucosidase, the plasma α-L-fucosidase (FUCA2), is known. To investigate the impact of both fucosidases in more detail, we generated two different monoclonal antibodies as useful tools for the detection of human and murine FUCA1 and utilized a FUCA2-specific antibody to demonstrate that FUCA2 is a bona fide lysosomal protein that is sorted in a mannose 6-phosphate (M6P)-dependent manner. We then compared FUCA1 and FUCA2 upon ectopic expression and evaluated their enzyme activity profiles under various conditions. Untagged and differently tagged versions of FUCA1 exhibited α-L-fucosidase activity, while various FUCA2 derivatives, even after affinity purification, did not show any fucosidase activity against commonly used pseudo-substrates. Our findings suggest that FUCA1 and not FUCA2 is exclusively responsible for the lysosomal de-fucosylation of glycoconjugates. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lysosomal Storage Disorders)
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23 pages, 5386 KB  
Article
Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants
by Antje Banning, Lukas Hoeren, Isis Atallah, Ralph Orczyk, David Jacquier, Diana Ballhausen and Ritva Tikkanen
Cells 2025, 14(13), 1036; https://doi.org/10.3390/cells14131036 - 7 Jul 2025
Viewed by 524
Abstract
NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins [...] Read more.
NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins before their proteasomal degradation and in the activation of transcription factors that control the expression of proteasomal subunits. Here, we have characterized the pathogenic NGLY1 variants found in three Swiss NGLY deficiency patients, as well as the most common pathogenic NGLY1 variant, Arg401*, found in about 20% of patients. Our functional and structural assessments of these variants show that they cause a profound reduction in NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1. Furthermore, transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants. Our in silico structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390 and potentially impairment of protein–protein interactions. Our results provide important information on the functional and structural effects of pathogenic NGLY1 variants and pave the way for structure-based development of personalized treatment options. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lysosomal Storage Disorders)
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21 pages, 6133 KB  
Article
Residual Cystine Transport Activity for Specific Infantile and Juvenile CTNS Mutations in a PTEC-Based Addback Model
by Louise Medaer, Dries David, Maxime Smits, Elena Levtchenko, Maurilio Sampaolesi and Rik Gijsbers
Cells 2024, 13(7), 646; https://doi.org/10.3390/cells13070646 - 6 Apr 2024
Viewed by 2294
Abstract
Cystinosis is a rare, autosomal recessive, lysosomal storage disease caused by mutations in the gene CTNS, leading to cystine accumulation in the lysosomes. While cysteamine lowers the cystine levels, it does not cure the disease, suggesting that CTNS exerts additional functions besides [...] Read more.
Cystinosis is a rare, autosomal recessive, lysosomal storage disease caused by mutations in the gene CTNS, leading to cystine accumulation in the lysosomes. While cysteamine lowers the cystine levels, it does not cure the disease, suggesting that CTNS exerts additional functions besides cystine transport. This study investigated the impact of infantile and juvenile CTNS mutations with discrepant genotype/phenotype correlations on CTNS expression, and subcellular localisation and function in clinically relevant cystinosis cell models to better understand the link between genotype and CTNS function. Using CTNS-depleted proximal tubule epithelial cells and patient-derived fibroblasts, we expressed a selection of CTNSmutants under various promoters. EF1a-driven expression led to substantial overexpression, resulting in CTNS protein levels that localised to the lysosomal compartment. All CTNSmutants tested also reversed cystine accumulation, indicating that CTNSmutants still exert transport activity, possibly due to the overexpression conditions. Surprisingly, even CTNSmutants expression driven by the less potent CTNS and EFS promoters reversed the cystine accumulation, contrary to the CTNSG339R missense mutant. Taken together, our findings shed new light on CTNS mutations, highlighting the need for robust assessment methodologies in clinically relevant cellular models and thus paving the way for better stratification of cystinosis patients, and advocating for the development of more personalized therapy. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lysosomal Storage Disorders)
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21 pages, 4505 KB  
Article
Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy
by Dar-Shong Lin, Yu-Wen Huang, Tsung-Han Lee, Lung Chang, Zon-Darr Huang, Tsu-Yen Wu, Tuan-Jen Wang and Che-Sheng Ho
Cells 2023, 12(7), 993; https://doi.org/10.3390/cells12070993 - 24 Mar 2023
Cited by 10 | Viewed by 2772
Abstract
We have shown in vivo and in vitro previously that psychosine causes dysfunction of autophagy and the ubiquitin-proteasome system underlying the pathogenesis of globoid cell leukodystrophy (GLD), a devastating lysosomal storage disease complicated by global demyelination. Here, we investigated the therapeutic efficacy of [...] Read more.
We have shown in vivo and in vitro previously that psychosine causes dysfunction of autophagy and the ubiquitin-proteasome system underlying the pathogenesis of globoid cell leukodystrophy (GLD), a devastating lysosomal storage disease complicated by global demyelination. Here, we investigated the therapeutic efficacy of the mTOR inhibitor rapamycin in twitcher mice, a murine model of infantile GLD, in biochemical, histochemical, and clinical aspects. Administration of rapamycin to twitcher mice inhibited mTOR signaling in the brains, and significantly reduced the accumulation of insoluble ubiquitinated protein and the formation of ubiquitin aggregates. The astrocytes and microglia reactivity were attenuated in that reactive astrocytes, ameboid microglia, and globoid cells were reduced in the brains of rapamycin-treated twitcher mice. Furthermore, rapamycin improved the cortical myelination, neurite density, and rescued the network complexity in the cortex of twitcher mice. The therapeutic action of rapamycin on the pathology of the twitcher mice’s brains prolonged the longevity of treated twitcher mice. Overall, these findings validate the therapeutic efficacy of rapamycin and highlight enhancing degradation of aggregates as a therapeutic strategy to modulate neuroinflammation, demyelination, and disease progression of GLD and other leukodystrophies associated with intracellular aggregates. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lysosomal Storage Disorders)
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