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Special Issue "Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editors

Prof. Dr. Mercè Pallas Lliberia
E-Mail Website
Guest Editor
Universitat de Barcelona, Barcelona, Spain
Interests: Ageing; Neurodegeneration; Alzheimer's disease; Neuropharmacology; Oxidative stress; Mitochondria; Proteostasis; Epigenetics
Special Issues and Collections in MDPI journals
Dr. Daniel Ortuño-Sahagún
E-Mail
Guest Editor
Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de las Salud (CUCS), Universidad de Guadalajara, Sierra Mojada No. 950, Col. Independencia, Guadalajara, 44340, Jalisco, Mexico
Interests: Gene Expresion Profiles; Neurodegenerative Diseases; Aging; Neuromodulation; Immunomodulation; Neuroimmune molecular basis; Epigenetics
Special Issues and Collections in MDPI journals
Dr. Christian Griñan- Ferre
E-Mail
Guest Editor
Universitat de Barcelona, Barcelona, Spain

Special Issue Information

Dear Colleagues,

Niemann–Pick disease Type C (NPC) is an autosomal recessive neurodegenerative disease with a progressive and fatal outcome. Due to its low incidence, i is classified as rare disease, with no effective treatment so far. Today, the denomination designates disorders characterized by unique abnormalities in intracellular cholesterol transport by endocytic trafficking with sequestration of unesterified cholesterol in late endosomes/lysosomes. However, significant advances that led to the elucidation of this disease occurred after the description of the two underlying genes NPC1 and NPC2, with 95% of cases associated to mutations in NPC1.

The disease is mostly diagnosed during childhood and progresses to life-threatening complications early in life; patients typically display cerebellar ataxia, difficulty speaking and swallowing, with progressive dementia. Histopathological hallmarks for NPC include the endosomal/lysosomal system with aberrant cholesterol and glycosphingolipids accumulation. Those are key symptoms and signs for NPC diagnosis and are also easy to follow both clinically and experimentally. However, we are still far from understanding how the loss of NPC1 function leads to signs and to the development of the disease.

This Special Issue is focused on the breakthroughs on NPC knowledge from a molecular point of view up to the therapeutic approach. Not only is basic research in animal models necessary to dissect the role of the NPC1 gene in physiological and pathological conditions, but also applied clinical research is mandatory in order to reach the cutting edge of scientific advances that will finally benefit patients, and the sooner this happens, the better.

Prof. Dr. Mercè Lliberia
Dr. Daniel Ortuño-Sahagún
Dr. Christian Griñan- Ferre
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Niemann–Pick C
  • Rare diseases
  • Lysosomal storage
  • Neurodegeneration
  • Cerebellar degeneration
  • Sphingomyelinase
  • Orphan disease
  • Therapy

Related Special Issue

Published Papers (4 papers)

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Research

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Open AccessArticle
Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T
Int. J. Mol. Sci. 2021, 22(8), 4009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084009 - 13 Apr 2021
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Abstract
Niemann-Pick type C2 (NP-C2) disease is a rare hereditary disease caused by mutations in the NPC2 gene. NPC2 is a small, soluble protein consisting of 151 amino acids, primarily expressed in late endosomes and lysosomes (LE/LY). Together with NPC1, a transmembrane protein found [...] Read more.
Niemann-Pick type C2 (NP-C2) disease is a rare hereditary disease caused by mutations in the NPC2 gene. NPC2 is a small, soluble protein consisting of 151 amino acids, primarily expressed in late endosomes and lysosomes (LE/LY). Together with NPC1, a transmembrane protein found in these organelles, NPC2 accomplishes the exclusion of cholesterol; thus, both proteins are essential to maintain cellular cholesterol homeostasis. Consequently, mutations in the NPC2 or NPC1 gene result in pathophysiological accumulation of cholesterol and sphingolipids in LE/LY. The vast majority of Niemann-Pick type C disease patients, 95%, suffer from a mutation of NPC1, and only 5% display a mutation of NPC2. The biochemical phenotype of NP-C1 and NP-C2 appears to be indistinguishable, and both diseases share several commonalities in the clinical manifestation. Studies of the pathological mechanisms underlying NP-C2 are mostly based on NP-C2 animal models and NP-C2 patient-derived fibroblasts. Recently, we established induced pluripotent stem cells (iPSCs), derived from a donor carrying the NPC2 mutations c.58G>T/c.140G>T. Here, we present a profile of pathophysiological in vitro features, shared by NP-C1 and NP-C2, of neural differentiated cells obtained from the patient specific iPSCs. Profiling comprised a determination of the NPC2 protein level, detection of cholesterol accumulation by filipin staining, analysis of oxidative stress, and determination of autophagy. As expected, the NPC2-deficient cells displayed a significantly reduced amount of NPC2 protein, and, accordingly, we observed a significantly increased amount of cholesterol. Most notably, NPC2-deficient cells displayed only a slight increase of reactive oxygen species (ROS), suggesting that they do not suffer from oxidative stress and express catalase at a high level. As a site note, comparable NPC1-deficient cells suffer from a lack of catalase and display an increased level of ROS. In summary, this cell line provides a valuable tool to gain deeper understanding, not only of the pathogenic mechanism of NP-C2, but also of NP-C1. Full article
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Open AccessArticle
Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease
Int. J. Mol. Sci. 2021, 22(7), 3409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073409 - 26 Mar 2021
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Abstract
Niemann–Pick type C (NPC) disease is a rare autosomal recessive inherited childhood neurodegenerative disease characterized by the accumulation of cholesterol and glycosphingolipids, involving the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 12-diols, exerts [...] Read more.
Niemann–Pick type C (NPC) disease is a rare autosomal recessive inherited childhood neurodegenerative disease characterized by the accumulation of cholesterol and glycosphingolipids, involving the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 12-diols, exerts beneficial effects in modulating inflammation and autophagy, critical features of the NPC disease. This study aims to evaluate the effects of UB-EV-52, an sEH inhibitor (sEHi), in an NPC mouse model (Npc) by administering it for 4 weeks (5 mg/kg/day). Behavioral and cognitive tests (open-field test (OF)), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that the treatment produced an improvement in short- and long-term memory as well as in spatial memory. Furthermore, UB-EV-52 treatment increased body weight and lifespan by 25% and reduced gene expression of the inflammatory markers (i.e., Il-1β and Mcp1) and enhanced oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. As for autophagic markers, surprisingly, we found significantly reduced levels of LC3B-II/LC3B-I ratio and significantly reduced brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in treated Npc mice group compared to untreated ones in hippocampal tissue. Lipid profile analysis showed a significant reduction of lipid storage in the liver and some slight changes in homogenated brain tissue in the treated NPC mice compared to the untreated groups. Therefore, our results suggest that pharmacological inhibition of sEH ameliorates most of the characteristic features of NPC mice, demonstrating that sEH can be considered a potential therapeutic target for this disease. Full article
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Open AccessArticle
Intracerebroventricular Treatment with 2-Hydroxypropyl-β-Cyclodextrin Decreased Cerebellar and Hepatic Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Expression in Niemann–Pick Disease Type C Model Mice
Int. J. Mol. Sci. 2021, 22(1), 452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010452 - 05 Jan 2021
Cited by 1 | Viewed by 851
Abstract
Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein [...] Read more.
Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-β-CD in Npc1 gene-deficient (Npc1−/−) mice. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in Npc1−/− mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1−/− mice. Repeated doses of intracerebroventricular HP-β-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1−/− mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-β-CD treatment. Full article
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Review

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Open AccessReview
Understanding and Treating Niemann–Pick Type C Disease: Models Matter
Int. J. Mol. Sci. 2020, 21(23), 8979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238979 - 26 Nov 2020
Cited by 1 | Viewed by 868
Abstract
Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C [...] Read more.
Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal–lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics. Full article
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