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

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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 July 2020) | Viewed by 50282

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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
Special Issues, Collections and Topics in MDPI journals

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
Special Issues, Collections and Topics in MDPI journals

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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, it 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. MERCÈ PALLAS LLIBERIA
Dr. Daniel Ortuño-Sahagún
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- 2nd Edition in International Journal of Molecular Sciences (7 articles)

Published Papers (14 papers)

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30 pages, 6115 KiB

Open AccessArticle

Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1

by Carsten Holzmann, Martin Witt, Arndt Rolfs, Veronica Antipova and Andreas Wree

Int. J. Mol. Sci. 2021, 22(5), 2539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052539 - 03 Mar 2021

Cited by 7 | Viewed by 2926

Abstract

In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1^−/− mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1^−/− and 123 NPC1^+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1^−/− mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1^−/− mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1^−/− mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1^−/− mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC^+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1^−/− mice was almost completely reduced only in the female groups. Full article

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

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13 pages, 1442 KiB

Open AccessArticle

Oxidative Stress and Alterations in the Antioxidative Defense System in Neuronal Cells Derived from NPC1 Patient-Specific Induced Pluripotent Stem Cells

by Alexandra V. Jürs, Christin Völkner, Maik Liedtke, Katharina Huth, Jan Lukas, Andreas Hermann and Moritz J. Frech

Int. J. Mol. Sci. 2020, 21(20), 7667; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207667 - 16 Oct 2020

Cited by 9 | Viewed by 2466

Abstract

Oxidative stress (OS) represents a state of an imbalanced amount of reactive oxygen species (ROS) and/or a hampered efficacy of the antioxidative defense system. Cells of the central nervous system are particularly sensitive to OS, as they have a massive need of oxygen to maintain proper function. Consequently, OS represents a common pathophysiological hallmark of neurodegenerative diseases and is discussed to contribute to the neurodegeneration observed amongst others in Alzheimer’s disease and Parkinson’s disease. In this context, accumulating evidence suggests that OS is involved in the pathophysiology of Niemann-Pick type C1 disease (NPC1). NPC1, a rare hereditary neurodegenerative disease, belongs to the family of lysosomal storage disorders. A major hallmark of the disease is the accumulation of cholesterol and other glycosphingolipids in lysosomes. Several studies describe OS both in murine in vivo and in vitro NPC1 models. However, studies based on human cells are limited to NPC1 patient-derived fibroblasts. Thus, we analyzed OS in a human neuronal model based on NPC1 patient-specific induced pluripotent stem cells (iPSCs). Higher ROS levels, as determined by DCF (dichlorodihydrofluorescein) fluorescence, indicated oxidative stress in all NPC1-deficient cell lines. This finding was further supported by reduced superoxide dismutase (SOD) activity. The analysis of mRNA and protein levels of SOD1 and SOD2 did not reveal any difference between control cells and NPC1-deficient cells. Interestingly, we observed a striking decrease in catalase mRNA and protein levels in all NPC1-deficient cell lines. As catalase is a key enzyme of the cellular antioxidative defense system, we concluded that the lack of catalase contributes to the elevated ROS levels observed in NPC1-deficient cells. Thus, a restitution of a physiological catalase level may pose an intervention strategy to rescue NPC1-deficient cells from the repercussions of oxidative stress contributing to the neurodegeneration observed in NPC1. Full article

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

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23 pages, 3592 KiB

Open AccessArticle

Single Cell Transcriptome Analysis of Niemann–Pick Disease, Type C1 Cerebella

by Antony Cougnoux, Julia C. Yerger, Mason Fellmeth, Jenny Serra-Vinardell, Kyle Martin, Fatemeh Navid, James Iben, Christopher A. Wassif, Niamh X. Cawley and Forbes D. Porter

Int. J. Mol. Sci. 2020, 21(15), 5368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155368 - 28 Jul 2020

Cited by 17 | Viewed by 4508

Abstract

Niemann–Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol and decreased cellular cholesterol bioavailability. A cardinal symptom of NPC1 is cerebellar ataxia due to Purkinje neuron loss. To gain an understanding of the cerebellar neuropathology we obtained single cell transcriptome data from control (Npc1^+/+) and both three-week-old presymptomatic and seven-week-old symptomatic mutant (Npc1^−/−) mice. In seven-week-old Npc1^−/− mice, differential expression data was obtained for neuronal, glial, vascular, and myeloid cells. As anticipated, we observed microglial activation and increased expression of innate immunity genes. We also observed increased expression of innate immunity genes by other cerebellar cell types, including Purkinje neurons. Whereas neuroinflammation mediated by microglia may have both neuroprotective and neurotoxic components, the contribution of increased expression of these genes by non-immune cells to NPC1 pathology is not known. It is possible that dysregulated expression of innate immunity genes by non-immune cells is neurotoxic. We did not anticipate a general lack of transcriptomic changes in cells other than microglia from presymptomatic three-week-old Npc1^−/− mice. This observation suggests that microglia activation precedes neuronal dysfunction. The data presented in this paper will be useful for generating testable hypotheses related to disease progression and Purkinje neurons loss as well as providing insight into potential novel therapeutic interventions. Full article

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

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14 pages, 2937 KiB

Open AccessArticle

Cholesterol Transport in Wild-Type NPC1 and P691S: Molecular Dynamics Simulations Reveal Changes in Dynamical Behavior

by Nadia Elghobashi-Meinhardt

Int. J. Mol. Sci. 2020, 21(8), 2962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082962 - 22 Apr 2020

Cited by 9 | Viewed by 2709

Abstract

The Niemann–Pick C1 (NPC1) protein is the main protein involved in NPC disease, a fatal lysosomal lipid storage disease. NPC1, containing 1278 amino acids, is comprised of three lumenal domains (N-terminal, middle lumenal, C-terminal) and a transmembrane (TM) domain that contains a five helix bundle referred to as the sterol-sensing domain (SSD). The exact purpose of the SSD is not known, but it is believed that the SSD may bind cholesterol, either as a part of the lipid trafficking pathway or as part of a signaling mechanism. A recent cryo-EM structure has revealed an itraconazole binding site (IBS) in the SSD of human NPC1. Using this structural data, we constructed a model of cholesterol-bound wild-type (WT) and mutant P691S and performed molecular dynamics (MD) simulations of each cholesterol-bound protein. For WT NPC1, cholesterol migrates laterally, in the direction of the lipid bilayer. In the case of P691S, cholesterol is observed for the first time to migrate away from the SSD toward the N-terminal domain via a putative tunnel that connects the IBS with the lumenal domains. Structural features of the IBS are analyzed to identify the causes for different dynamical behavior between cholesterol-bound WT and cholesterol-bound P691S. The side chain of Ser691 in the P691S mutant introduces a hydrogen bond network that is not present in the WT protein. This change is likely responsible for the altered dynamical behavior observed in the P691S mutant and helps explain the disrupted cholesterol trafficking behavior observed in experiments. Full article

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

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13 pages, 1152 KiB

Open AccessArticle

Evaluation of the Potential Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Niemann–Pick Disease, Type C1

by Niamh X. Cawley, Anna T. Lyons, Daniel Abebe, Christopher A. Wassif and Forbes D. Porter

Int. J. Mol. Sci. 2020, 21(7), 2430; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072430 - 31 Mar 2020

Cited by 7 | Viewed by 2250

Abstract

Niemann–Pick disease, type C1, is a cholesterol storage disease where unesterified cholesterol accumulates intracellularly. In the cerebellum this causes neurodegeneration of the Purkinje neurons that die in an anterior-to-posterior and time-dependent manner. This results in cerebellar ataxia as one of the major outcomes of the disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a significant role in the regulation of serum cholesterol levels by modulating LDL receptor levels on peripheral tissues. In the central nervous system, PCSK9 may have a similar effect on the closely related VLDL and ApoE2 receptors to regulate brain cholesterol. In addition, regulation of VLDLR and ApoER2 by PCSK9 may contribute to neuronal apoptotic pathways through Reelin, the primary ligand of VLDLR and ApoER2. Defects in reelin signaling results in cerebellar dysfunction leading to ataxia as seen in the Reeler mouse. Our recent findings that Pcsk9 is expressed ~8-fold higher in the anterior lobules of the cerebellum compared to the posterior lobule X, which is resistant to neurodegeneration, prompted us to ask whether PCSK9 could play a role in NPC1 disease progression. We addressed this question genetically, by characterizing NPC1 disease in the presence or absence of PCSK9. Analysis of double mutant Pcsk9^-/-/Npc1^-/- mice by disease severity scoring, motor assessments, lifespan, and cerebellar Purkinje cell staining, showed no obvious difference in NPC1 disease progression with that of Npc1^-/- mice. This suggests that PCSK9 does not play an apparent role in NPC1 disease progression. Full article

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

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11 pages, 1646 KiB

Open AccessArticle

Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage

by Andrés D. Klein, Javier González de la Vega and Silvana Zanlungo

Int. J. Mol. Sci. 2020, 21(6), 2127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062127 - 20 Mar 2020

Cited by 9 | Viewed by 2693

Abstract

Niemann–Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann–Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann–Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease. Full article

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

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13 pages, 2741 KiB

Open AccessArticle

Different Trafficking Phenotypes of Niemann-Pick C1 Gene Mutations Correlate with Various Alterations in Lipid Storage, Membrane Composition and Miglustat Amenability

by Graham Brogden, Hadeel Shammas, Friederike Walters, Katia Maalouf, Anibh M. Das, Hassan Y. Naim and Sandra Rizk

Int. J. Mol. Sci. 2020, 21(6), 2101; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062101 - 19 Mar 2020

Cited by 8 | Viewed by 3228

Abstract

Niemann-Pick Type C (NPC) is an autosomal recessive lysosomal storage disease leading to progressive neurodegeneration. Mutations in the NPC1 gene, which accounts for 95% of the cases, lead to a defect in intra-lysosomal trafficking of cholesterol and an accumulation of storage material including cholesterol and sphingolipids in the endo-lysosomal system. Symptoms are progressive neurological and visceral deterioration, with variable onset and severity of the disease. This study investigates the influence of two different NPC1 mutations on the biochemical phenotype in fibroblasts isolated from NPC patients in comparison to healthy, wild type (WT) cells. Skin derived fibroblasts were cultured from one patient compound-heterozygous for D874V/D948Y mutations, which presented wild-type like intracellular trafficking of NPC1, and a second patient compound- heterozygous for I1061T/P887L mutations, which exhibited a more severe biochemical phenotype as revealed in the delayed trafficking of NPC1. Biochemical analysis using HPLC and TLC indicated that lipid accumulations were mutation-dependent and correlated with the trafficking pattern of NPC1: higher levels of cholesterol and glycolipids were associated with the mutations that exhibited delayed intracellular trafficking, as compared to their WT-like trafficked or wild type (WT) counterparts. Furthermore, variations in membrane structure was confirmed in these cell lines based on alteration in lipid rafts composition as revealed by the shift in flotillin-2 (FLOT2) distribution, a typical lipid rafts marker, which again showed marked alterations only in the NPC1 mutant showing major trafficking delay. Finally, treatment with N-butyldeoxynojirimycin (NB-DNJ, Miglustat) led to a reduction of stored lipids in cells from both patients to various extents, however, no normalisation in lipid raft structure was achieved. The data presented in this study help in understanding the varying biochemical phenotypes observed in patients harbouring different mutations, which explain why the effectiveness of NB-DNJ treatment is patient specific. Full article

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

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12 pages, 1791 KiB

Open AccessArticle

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

by Sanzana Hoque, Yuki Kondo, Nodoka Sakata, Yusei Yamada, Madoka Fukaura, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Katsumi Higaki, Akio Hayashi, Takaki Komiya, Yoichi Ishitsuka and Tetsumi Irie

Int. J. Mol. Sci. 2020, 21(3), 898; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030898 - 30 Jan 2020

Cited by 15 | Viewed by 3037

Abstract

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-β-CD, HP-γ-CD, and their homolog 2-hydroxypropyl-α-cyclodextrin (HP-α-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-β-CD and HP-γ-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells. Full article

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

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26 pages, 4286 KiB

Open AccessArticle

Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1

by Kyle B. Martin, Ian M. Williams, Celine V. Cluzeau, Antony Cougnoux, Ryan K. Dale, James R. Iben, Niamh X. Cawley, Christopher A. Wassif and Forbes D. Porter

Int. J. Mol. Sci. 2020, 21(1), 292; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010292 - 31 Dec 2019

Cited by 17 | Viewed by 4328

Abstract

Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by progressive cerebellar ataxia. In NPC1, a defect in cholesterol transport leads to endolysosomal storage of cholesterol and decreased cholesterol bioavailability. Purkinje neurons are sensitive to the loss of NPC1 function. However, degeneration of Purkinje neurons is not uniform. They are typically lost in an anterior-to-posterior gradient with neurons in lobule X being resistant to neurodegeneration. To gain mechanistic insight into factors that protect or potentiate Purkinje neuron loss, we compared RNA expression in cerebellar lobules III, VI, and X from control and mutant mice. An unexpected finding was that the gene expression differences between lobules III/VI and X were more pronounced than those observed between mutant and control mice. Functional analysis of genes with anterior to posterior gene expression differences revealed an enrichment of genes related to neuronal cell survival within the posterior cerebellum. This finding is consistent with the observation, in multiple diseases, that posterior Purkinje neurons are, in general, resistant to neurodegeneration. To our knowledge, this is the first study to evaluate anterior to posterior transcriptome-wide changes in gene expression in the cerebellum. Our data can be used to not only explore potential pathological mechanisms in NPC1, but also to further understand cerebellar biology. Full article

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

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12 pages, 3250 KiB

Open AccessArticle

Alteration of GABAergic Input Precedes Neurodegeneration of Cerebellar Purkinje Cells of NPC1-Deficient Mice

by Michael Rabenstein, Nico Murr, Andreas Hermann, Arndt Rolfs and Moritz J. Frech

Int. J. Mol. Sci. 2019, 20(24), 6288; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246288 - 13 Dec 2019

Cited by 7 | Viewed by 2643

Abstract

Niemann-Pick Disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease belonging to the family of lysosomal storage disorders. NPC1-patients suffer from, amongst other symptoms, ataxia, based on the dysfunction and loss of cerebellar Purkinje cells. Alterations in synaptic transmission are believed to contribute to a pathological mechanism leading to the progressive loss of Purkinje cells observed in NPC1-deficient mice. With regard to inhibitory synaptic transmission, alterations of GABAergic synapses are described but functional data are missing. For this reason, we have examined here the inhibitory GABAergic synaptic transmission of Purkinje cells of NPC1-deficient mice (NPC1^−/−). Patch clamp recordings of inhibitory post-synaptic currents (IPSCs) of Purkinje cells revealed an increased frequency of GABAergic IPSCs in NPC1^−/− mice. In addition, Purkinje cells of NPC1^−/− mice were less amenable for modulation of synaptic transmission via the activation of excitatory NMDA-receptors (NMDA-Rs). Western blot testing disclosed a reduced protein level of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) subunit GluA2 in the cerebella of NPC1^−/− mice, indicating a disturbance in the internalization of GluA2-containing AMPA-Rs. Since this is triggered by the activation of NMDA-Rs, we conclude that a disturbance in the synaptic turnover of AMPA-Rs underlies the defective inhibitory GABAergic synaptic transmission. While these alterations precede obvious signs of neurodegeneration of Purkinje cells, we propose a contribution of synaptic malfunction to the initiation of the loss of Purkinje cells in NPC1. Thus, a prevention of the disturbance of synaptic transmission in early stages of the disease might display a target with which to avert progressive neurodegeneration in NPC1. Full article

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

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16 pages, 1508 KiB

Open AccessArticle

Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann–Pick Disease Type C

by Masamitsu Maekawa, Isamu Jinnoh, Yotaro Matsumoto, Aya Narita, Ryuichi Mashima, Hidenori Takahashi, Anna Iwahori, Daisuke Saigusa, Kumiko Fujii, Ai Abe, Katsumi Higaki, Shosei Yamauchi, Yuji Ozeki, Kazutaka Shimoda, Yoshihisa Tomioka, Torayuki Okuyama, Yoshikatsu Eto, Kousaku Ohno, Peter T Clayton, Hiroaki Yamaguchi and Nariyasu Mano Show full author list Hide full author list

Int. J. Mol. Sci. 2019, 20(20), 5018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205018 - 10 Oct 2019

Cited by 24 | Viewed by 5712

Abstract

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder caused by the mutation of cholesterol-transporting proteins. In addition, early treatment is important for good prognosis of this disease because of the progressive neurodegeneration. However, the diagnosis of this disease is difficult due to a variety of clinical spectrum. Lysosphingomyelin-509, which is one of the most useful biomarkers for NPC, was applied for the rapid and easy detection of NPC. The fact that its chemical structure was unknown until recently implicates the unrevealed pathophysiology and molecular mechanisms of NPC. In this study, we aimed to elucidate the structure of lysosphingomyelin-509 by various mass spectrometric techniques. As our identification strategy, we adopted analytical and organic chemistry approaches to the serum of patients with NPC. Chemical derivatization and hydrogen abstraction dissociation–tandem mass spectrometry were used for the determination of function groups and partial structure, respectively. As a result, we revealed the exact structure of lysosphingomyelin-509 as N-acylated and O-phosphocholine adducted serine. Additionally, we found that a group of metabolites with N-acyl groups were increased considerably in the serum/plasma of patients with NPC as compared to that of other groups using targeted lipidomics analysis. Our techniques were useful for the identification of lysosphingomyelin-509. Full article

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

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Review

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34 pages, 3240 KiB

Open AccessReview

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

by Berna Seker Yilmaz, Julien Baruteau, Ahad A. Rahim and Paul Gissen

Int. J. Mol. Sci. 2020, 21(14), 5059; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145059 - 17 Jul 2020

Cited by 22 | Viewed by 3484

Abstract

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials. Full article

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

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37 pages, 3164 KiB

Open AccessReview

Metabolomic Studies of Lipid Storage Disorders, with Special Reference to Niemann-Pick Type C Disease: A Critical Review with Future Perspectives

by Benita Claire Percival, Miles Gibson, Philippe B. Wilson, Frances M. Platt and Martin Grootveld

Int. J. Mol. Sci. 2020, 21(7), 2533; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072533 - 05 Apr 2020

Cited by 13 | Viewed by 4163

Abstract

Lysosomal storage disorders (LSDs) are predominantly very rare recessive autosomal neurodegenerative diseases.Sphingolipidoses, a sub-group of LSDs, result from defects in lysosomal enzymes involved in sphingolipid catabolism, and feature disrupted storage systems which trigger complex pathogenic cascades with other organelles collaterally affected. This process leads to cell dysfunction and death, particularly in the central nervous system. One valuable approach to gaining insights into the global impact of lysosomal dysfunction is through metabolomics, which represents a discovery tool for investigating disease-induced modifications in the patterns of large numbers of simultaneously-analysed metabolites, which also features the identification of biomarkers Here, the scope and applications of metabolomics strategies to the investigation of sphingolipidoses is explored in order to facilitate our understanding of the biomolecular basis of these conditions. This review therefore surveys the benefits of applying ’state-of-the-art’ metabolomics strategies, both univariate and multivariate, to sphingolipidoses, particularly Niemann-Pick type C disease. Relevant limitations of these techniques are also discussed, along with the latest advances and developments. We conclude that metabolomics strategies are highly valuable, distinctive bioanalytical techniques for probing LSDs, most especially for the detection and validation of potential biomarkers. They also show much promise for monitoring disease progression and the evaluation of therapeutic strategies and targets. Full article

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

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Open AccessReview

Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann–Pick Disease Type C1

by Anja U. Bräuer, Angela Kuhla, Carsten Holzmann, Andreas Wree and Martin Witt

Int. J. Mol. Sci. 2019, 20(18), 4392; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184392 - 06 Sep 2019

Cited by 27 | Viewed by 4747

Abstract

Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann–Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options. Full article

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

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