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Cells
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Lysosomal Storage Disease: From Molecular Mechanisms to Therapeutic Opportunities
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Lysosomal Storage Disease: From Molecular Mechanisms to Therapeutic Opportunities

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

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 5621

Special Issue Editor

Prof. Ingeborg Krägeloh-Mann

E-Mail Website
Guest Editor
Department of Pediatric Neurology, University Children's Hospital Tübingen, 72076 Tübingen, Germany
Interests: clinical, biochemical, and genetic characterization of sphingolipidoses (metachromatic leukodystrophy, M. Krabbe, NP-C, and gangliosidoses); standardized clinical description including neuroimaging with natural history and following therapy; neuroplasticity, reorganization, and vulnerability after early brain lesions; cerebral palsy.

Special Issue Information

Dear Colleagues,

Lysosomal storage disorders have been known for decades to be multisystem disorders with a variable onset and course. The degree to which the central nervous system is affected usually determines the severity and fatality of the disease. Although individual defects are very rare (usually with an incidence of <1:100,000), interest in these disorders is increasing. The molecular basis is increasingly being elucidated and therapeutic strategies are becoming more developed with growing expertise in targeted cellular and genetic therapies. This encourages the development of systematic and standardized approaches to capture the clinical features of these diseases and their natural history, including registries and biobanking. Early diagnosis represents a challenge as therapeutic effects can mainly be achieved early in the disease course. Quite recent is interest in the role of lysosomes in a number of adult neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease. Although not of monogenetic origin, heterozygous and homozygous mutations in lysosomal genes are amongst the highest genetic risk factors and lysosomal dysfunction may enhance the neurodegenerative process.

We invite you to contribute to this Special Issue of Cells, which is dedicated to these disorders. Contributions on cell biology, molecular biology, and biophysics are as welcome, as are clinical studies covering the natural history or therapeutic aspects.

Prof. Ingeborg Krägeloh-Mann
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • lysosomal storage disorders
  • neurodegeneration
  • cell biology
  • molecular biology
  • biophysics
  • therapeutic options
  • natural course

Published Papers (2 papers)

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Research

20 pages, 5709 KiB  
Article
Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis
by Jason Andrew Weesner, Ida Annunziata, Tianhong Yang, Walter Acosta, Elida Gomero, Huimin Hu, Diantha van de Vlekkert, Jorge Ayala, Xiaohui Qiu, Leigh Ellen Fremuth, David N. Radin, Carole L. Cramer and Alessandra d’Azzo
Cells 2022, 11(16), 2579; https://doi.org/10.3390/cells11162579 - 19 Aug 2022
Cited by 4 | Viewed by 2420
Abstract
GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 [...] Read more.
GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine β-Gal fused to the plant lectin subunit B of ricin (mβ-Gal:RTB). We show that long-term, bi-weekly systemic injection of mβ-Gal:RTB in the β-Gal−/− mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, β-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the β-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis. Full article
(This article belongs to the Special Issue Lysosomal Storage Disease: From Molecular Mechanisms to Therapeutic Opportunities)
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15 pages, 2907 KiB  
Article
Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease
by Yanyan Peng, Benjamin Liou, Yi Lin, Venette Fannin, Wujuan Zhang, Ricardo A. Feldman, Kenneth D. R. Setchell, Gregory A. Grabowski and Ying Sun
Cells 2021, 10(9), 2286; https://doi.org/10.3390/cells10092286 - 02 Sep 2021
Cited by 11 | Viewed by 2680
Abstract
Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in [...] Read more.
Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy–lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD. Full article
(This article belongs to the Special Issue Lysosomal Storage Disease: From Molecular Mechanisms to Therapeutic Opportunities)
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