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Journal ArticleDOI

Complex lipid trafficking in Niemann-Pick disease type C.

01 Jan 2015-Journal of Inherited Metabolic Disease (Springer Netherlands)-Vol. 38, Iss: 1, pp 187-199
TL;DR: A reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models is provided, with emphasis on differences between systemic organs and the brain.
Abstract: Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".
Citations
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Journal ArticleDOI
TL;DR: Ten genetically elucidated obesity syndromes are summarized and suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine are provided.
Abstract: In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.

289 citations

Journal ArticleDOI
02 Jun 2016-Cell
TL;DR: The structural and biochemical characterizations provided provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection.

251 citations


Cites background from "Complex lipid trafficking in Nieman..."

  • ...Genetic and biochemical characterizations revealed that NPC1 and NPC2 cooperate to export low density lipoprotein (LDL)-derived cholesterol from late endosomes and lysosomes to other cellular compartments (Infante et al., 2008; Sleat et al., 2004; Vanier, 2015)....

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Journal ArticleDOI
TL;DR: The current knowledge on dysregulated cholesterol homeostasis in NAFLD is summarized and the cellular mechanisms of hepatic FC toxicity and its contribution to ongoing liver injury in this disease are examined.

229 citations


Cites background from "Complex lipid trafficking in Nieman..."

  • ...A deficiency in NPC1 or NPC2 is responsible for Niemann–Pick type C disease, which is a rare neurovisceral disorder characterized by FC accumulation in most tissues, including the liver [170,171]....

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  • ...Niemann–Pick C1 and C2 proteins, NPC1 and NPC2, are involved in the trafficking of endocytosed lipoprotein cholesterol from the endolysosomal compartment to the rest of the cell [170,171]....

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Journal ArticleDOI
TL;DR: Clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients are developed that can inform care providers, care funders, patients and their carers of best practice of care.
Abstract: Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.

194 citations


Cites background from "Complex lipid trafficking in Nieman..."

  • ...Disease causing mutations in either gene result in tissue accumulation of multiple lipids (see Ref [8] for review)....

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  • ...References related to a single topic (i.e., Epidemiology, Genetics, Pathophysiology, Clinical Diagnosis, Laboratory, Imaging, Therapy, Recommendations) were pulled together and the GDG was divided into subgroups aimed to critically appraise references devoted to a specific topic....

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  • ...In addition, the European Metabolic Reference network (MetabERN) has adopted this guideline for the management of NPC patients within the network....

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  • ...Referral to a clinical geneticist or genetic counsellor should be considered upon the diagnosis of NPC. Strength of recommendation: 1 Level of evidence: A Experts opinion: completely agree (81%), mostly agree (19%), partially agree (0%), mostly disagree (0...

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Journal ArticleDOI
TL;DR: It is demonstrated that STARD3 induces cholesterol accumulation in endosomes at the expense of the plasma membrane, and is a cholesterol transporter scaffolding ER–endosome contacts and modulating cellular cholesterol repartition by delivering cholesterol to endosomal contacts.
Abstract: StAR‐related lipid transfer domain‐3 (STARD3) is a sterol‐binding protein that creates endoplasmic reticulum (ER)–endosome contact sites. How this protein, at the crossroad between sterol uptake and synthesis pathways, impacts the intracellular distribution of this lipid was ill‐defined. Here, by using in situ cholesterol labeling and quantification, we demonstrated that STARD3 induces cholesterol accumulation in endosomes at the expense of the plasma membrane. STARD3‐mediated cholesterol routing depends both on its lipid transfer activity and its ability to create ER–endosome contacts. Corroborating this, in vitro reconstitution assays indicated that STARD3 and its ER‐anchored partner, Vesicle‐associated membrane protein‐associated protein (VAP), assemble into a machine that allows a highly efficient transport of cholesterol within membrane contacts. Thus, STARD3 is a cholesterol transporter scaffolding ER–endosome contacts and modulating cellular cholesterol repartition by delivering cholesterol to endosomes.

168 citations

References
More filters
Book
01 Jan 1995
TL;DR: In this paper, the authors present a list of disorders of MITOCHONDRIAL FUNCTION, including the following: DISORDERS OF MIOCHONDRIC FERTILITY XIX, XVI, XIX.
Abstract: I. INTRODUCTION II. PERSPECTIVES III. GENERAL THEMES IV. CANCER V. CHROMOSOMES VI. DIAGNOSTIC APPROACHES VII. CARBOHYDRATES VIII. AMINO ACIDS IX. ORGANIC ACIDS X. DISORDERS OF MITOCHONDRIAL FUNCTION XI. PURINES AND PYRIMIDINES XII. LIPIDS XIII. PORPHYRINS XIV. METALS XV. PEROXISOMES XVI. LYSOSOMAL DISORDERS XVII. VITAMINS XVIII. HORMONES XIX. BLOOD XX. IMMUNE AND DEFENSE SYSTEMS XXI. MEMBRANE TRANSPORT DISORDERS XXII. CONNECTIVE TISSUE XXIII. CARDIOVASCULAR SYSTEM XXIV. KIDNEY XXV. MUSCLE XXVI. LUNG XXVII. SKIN XXVIII. NEUROGENETICS XXIX. EYE XXX. MULTISYSTEM INBORN ERRORS OF DEVELOPMENT

10,525 citations

Journal ArticleDOI
11 Jul 1997-Science
TL;DR: Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking.
Abstract: Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.

1,403 citations


"Complex lipid trafficking in Nieman..." refers background in this paper

  • ...The NPC1 and NPC2 genes were identified in 1997 and 2000, respectively (Carstea et al 1997; Naureckiene et al 2000)....

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Journal ArticleDOI
TL;DR: The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin, and genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis.
Abstract: Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

974 citations

Journal ArticleDOI
22 Dec 2000-Science
TL;DR: Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.
Abstract: Niemann-Pick type C2 disease (NP-C2) is a fatal hereditary disorder of unknown etiology characterized by defective egress of cholesterol from lysosomes. Here we show that the disease is caused by a deficiency in HE1, a ubiquitously expressed lysosomal protein identified previously as a cholesterol-binding protein. HE1 was undetectable in fibroblasts from NP-C2 patients but present in fibroblasts from unaffected controls and NP-C1 patients. Mutations in the HE1 gene, which maps to chromosome 14q24.3, were found in NP-C2 patients but not in controls. Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.

817 citations


"Complex lipid trafficking in Nieman..." refers background in this paper

  • ...The NPC1 and NPC2 genes were identified in 1997 and 2000, respectively (Carstea et al 1997; Naureckiene et al 2000)....

    [...]

  • ...At the time its causative role in NPC was discovered (Naureckiene et al 2000), HE1 had already been described as a cholesterol-binding protein....

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Journal ArticleDOI
TL;DR: It is found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells, which represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.
Abstract: Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.

762 citations


"Complex lipid trafficking in Nieman..." refers background in this paper

  • ...More recently, Platt and collaborators (Lloyd-Evans et al 2008) made the observation of a reduced calcium release from acidic compartments in NP-C lymphoblasts or fibroblasts, and showed that this could be recapitulated by treating RAW cells by 1 μM (but not 0.1 μM) sphingosine....

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  • ...…sphingoid bases are other offending metabolite candidates in pathogenesis of NPC. Low concentrations of amphiphilic amines, e.g., imipramine, U18666A, but also sphinganine (Roff et al 1991) or sphingosine (Lloyd-Evans et al 2008) added to normal cell cultures, can elicit an "NPC phenotype"....

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  • ...They found that the calcium defect (and sphingosine elevation) preceded alterations of glycosphingolipid trafficking and cholesterol storage, which led Platt's group to postulate that in NPC, sphingosine is the primary offending metabolite (Lloyd-Evans et al 2008)....

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