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

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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: closed (30 November 2021) | Viewed by 27612

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Prof. Dr. Mercè Lliberia

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Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona, 08028 Barcelona, Spain
Interests: ageing; neurodegeneration; alzheimer's disease; neuropharmacology; oxidative stress; mitochondria; proteostasis; epigenetics
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Dr. Daniel Ortuño-Sahagún

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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
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Dr. Christian Griñan- Ferre

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Universitat de Barcelona, Barcelona, Spain

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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

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Keywords

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

Related Special Issue

Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives in International Journal of Molecular Sciences (14 articles)

Published Papers (7 papers)

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Research

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41 pages, 9573 KiB

Open AccessArticle

Organ Weights in NPC1 Mutant Mice Partly Normalized by Various Pharmacological Treatment Approaches

by Veronica Antipova, Lisa-Marie Steinhoff, Carsten Holzmann, Arndt Rolfs, Carlos Junior Hempel, Martin Witt and Andreas Wree

Int. J. Mol. Sci. 2023, 24(1), 573; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010573 - 29 Dec 2022

Cited by 1 | Viewed by 2583

Abstract

Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the NPC1 leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-Npc1^m1N/-J Jackson Npc1 mice in female and male Npc1^+/+ and Npc1^−/− mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 Npc1^+/+, 175 Npc1^−/−) were dissected at P65. In both sexes, the body weights of None and Sham Npc1^−/− mice were lower than those of respective Npc1^+/+ mice. The influence of the Npc1 mutation and/or sex on the weights of various organs, however, differed considerably. In males, Npc1^+/+ and Npc1^−/− mice had comparable absolute weights of lungs, spleen, and adrenal glands. In Npc1^−/− mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female Npc1^−/− mice, ovaries, and uteri were significantly smaller. In Npc1^−/− mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies. Full article

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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27 pages, 7521 KiB

Open AccessArticle

Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation

by Kristina Dominko, Ana Rastija, Sandra Sobocanec, Lea Vidatic, Sarah Meglaj, Andrea Lovincic Babic, Birgit Hutter-Paier, Alessio-Vittorio Colombo, Stefan F. Lichtenthaler, Sabina Tahirovic and Silva Hecimovic

Int. J. Mol. Sci. 2021, 22(24), 13256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413256 - 09 Dec 2021

Cited by 8 | Viewed by 2720

Abstract

Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using NPC1-null cells, primary mouse NPC1-deficient neurons and NPC1-deficient mice (BALB/cNctr-Npc1m1N), we show that retromer function is impaired in NPC. This is manifested by altered transport of the retromer core components Vps26, Vps35 and/or retromer receptor sorLA and by retromer accumulation in neuronal processes, such as within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at the presymptomatic stage (at 4-weeks of age), indicating that the retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we show that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Thus, we characterized retromer dysfunction in NPC and propose that the rescue of retromer impairment may represent a novel therapeutic approach against NPC. Full article

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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15 pages, 2065 KiB

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

by Maik Liedtke, Christin Völkner, Alexandra V. Jürs, Franziska Peter, Michael Rabenstein, Andreas Hermann and Moritz J. Frech

Int. J. Mol. Sci. 2021, 22(8), 4009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084009 - 13 Apr 2021

Cited by 4 | Viewed by 2072

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 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

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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16 pages, 1590 KiB

Open AccessArticle

Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease

by Christian Griñán-Ferré, Júlia Companys-Alemany, Júlia Jarné-Ferrer, Sandra Codony, Celia González-Castillo, Daniel Ortuño-Sahagún, Lluïsa Vilageliu, Daniel Grinberg, Santiago Vázquez and Mercè Pallàs

Int. J. Mol. Sci. 2021, 22(7), 3409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073409 - 26 Mar 2021

Cited by 2 | Viewed by 2916

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 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

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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12 pages, 3317 KiB

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

by Madoka Fukaura, Yoichi Ishitsuka, Seiichi Shirakawa, Naoki Ushihama, Yusei Yamada, Yuki Kondo, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Yuki Kurauchi, Takahiro Seki, Hiroshi Katsuki, Katsumi Higaki, Muneaki Matsuo and Tetsumi Irie

Int. J. Mol. Sci. 2021, 22(1), 452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010452 - 05 Jan 2021

Cited by 18 | Viewed by 4141

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 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

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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Review

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20 pages, 2531 KiB

Open AccessReview

Neurodegeneration in Niemann–Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment

by Ida Cariati, Laura Masuelli, Roberto Bei, Virginia Tancredi, Claudio Frank and Giovanna D’Arcangelo

Int. J. Mol. Sci. 2021, 22(12), 6600; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126600 - 20 Jun 2021

Cited by 15 | Viewed by 6211

Abstract

Niemann–Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease. Full article

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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37 pages, 2112 KiB

Open AccessReview

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

by Valentina Pallottini and Frank W. Pfrieger

Int. J. Mol. Sci. 2020, 21(23), 8979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238979 - 26 Nov 2020

Cited by 18 | Viewed by 5541

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 (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

(This article belongs to the Special Issue Advances in Knowledge in Niemann-Pick Disease Type C: Facts and Perspectives- 2nd Edition)

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