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Methods Mol Biol 2019 ;1949:257-267

Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

Niemann-Pick C1 (NPC1) is a membrane protein required for the transport of low-density lipoprotein (LDL)-derived cholesterol from endosomes and lysosomes to the other organelles. Here, we describe the recombinant protein expression, purification, and characterization of the human NPC1. The protein is transiently expressed in human embryonic kidney (HEK) cells. Read More

Am J Physiol Cell Physiol 2019 Feb 21. Epub 2019 Feb 21.

Jesse Brown VA Medical Center, Chicago, Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.

Intestinal Niemann Pick C1 Like 1 (NPC1L1) protein plays a key role in cholesterol absorption. A decrease in NPC1L1 expression has been implicated in lowering plasma cholesterol and mitigating the risk for coronary heart disease. Little is known about the mechanisms responsible for NPC1L1 protein degradation that upon activation may lead to a reduction in NPC1L1 protein levels in intestinal epithelial cells (IECs). Read More

Elife 2019 Feb 18;8. Epub 2019 Feb 18.

Institute of Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany.

Perturbations in mitochondrial function and homeostasis are pervasive in lysosomal storage diseases, but the underlying mechanisms remain unknown. Here, we report a transcriptional program that represses mitochondrial biogenesis and function in lysosomal storage diseases Niemann-Pick type C (NPC) and acid sphingomyelinase deficiency (ASM), in patient cells and mouse tissues. This mechanism is mediated by the transcription factors KLF2 and ETV1, which are both induced in NPC and ASM patient cells. Read More

Ann Transl Med 2018 Dec;6(24):476

Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.

The lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders that are caused for the most part by enzyme deficiencies within the lysosome resulting in accumulation of undegraded substrate. This storage process leads to a broad spectrum of clinical manifestations depending on the specific substrate and site of accumulation. Examples of LSDs include the mucopolysaccharidoses, mucolipidoses, oligosaccharidoses, Pompe disease, Gaucher disease, Fabry disease, the Niemann-Pick disorders, and neuronal ceroid lipofuscinoses. Read More

Brain Dev 2019 Feb 5. Epub 2019 Feb 5.

Division of Neurology, National Center for Child Health and Development, Tokyo, Japan.

Background: Niemann-Pick type C (NPC) is a lysosomal lipid storage disease with mutation of NPC1/NPC2 genes, which transport lipids in the endosome and lysosome, and various neurological symptoms. NPC patients also develop hepatosplenomegaly or liver disorder in the neonatal period, and 10% suffer severe liver failure. Neonatal hemochromatosis (NH) is a liver disorder characterized by hepatic and extrahepatic siderosis. Read More

Int J Mol Sci 2019 Feb 7;20(3). Epub 2019 Feb 7.

School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.

The accumulation of lipids in the late endosomes and lysosomes of Niemann⁻Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel's voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that phosphoinositides are responsible for both the mislocalization of annexin A2 (AnxA2) and a soluble NSF (N-ethylmaleimide Sensitive Fusion) protein attachment receptor (SNARE) recycling defect. These results are set in the context of existing knowledge of NPCD to sketch an account of the endolysosomal pathology key to this disease. Read More

Orphanet J Rare Dis 2019 Feb 7;14(1):32. Epub 2019 Feb 7.

Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.

Background: Niemann-Pick disease Type C (NP-C) is a lysosomal lipid storage disorder characterized by progressive neurodegenerative symptomatology. The signs and symptoms of NP-C vary with age at disease onset, and available therapies are directed at alleviating symptoms and stabilizing disease progression. We report the characteristics and factors related to disease progression, and analyze the effect of miglustat treatment on disease progression and patient survival using NP-C disability scales. Read More

JCI Insight 2019 Feb 7;4(3). Epub 2019 Feb 7.

Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.

Quetiapine, one of the most prescribed atypical antipsychotics, has been associated with hyperlipidemia and an increased risk for cardiovascular disease in patients, but the underlying mechanisms remain unknown. Here, we identified quetiapine as a potent and selective agonist for pregnane X receptor (PXR), a key nuclear receptor that regulates xenobiotic metabolism in the liver and intestine. Recent studies have indicated that PXR also plays an important role in lipid homeostasis. Read More

J Audiol Otol 2019 Feb 8. Epub 2019 Feb 8.

Department of Otorhinolaryngology, Boramae Medical Center, Seoul Metropolitan Government-Seoul National University, Seoul, Korea.

Background And Objectives: The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-β-cyclodextrin (HPβCD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HPβCD could partially resolve the symptoms in both animals and human patients. Read More

Yakugaku Zasshi 2019 ;139(2):143-155

Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU).

Recently, the application of β-cyclodextrins (β-CDs) as therapeutic agents has received considerable attention. β-CDs have been reported to have therapeutic effects on various diseases, such as Niemann-Pick type C (NPC) disease, a family of lysosomal storage disorders characterized by the lysosomal accumulation of cholesterol. To further improve the therapeutic efficacy of β-CDs, the use of β-CD-threaded polyrotaxanes (PRXs) has been proposed as a carrier of β-CDs for NPC disease. Read More

J Biol Chem 2019 Feb;294(5):1706-1709

From the Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305-5307

Low-density lipoprotein particles are taken up by cells and delivered to the lysosome where their cholesterol esters are cleaved off by acid lipase. The released, free cholesterol is then exported from lysosomes for cellular needs or storage. This article summarizes recent advances in our understanding of the molecular basis of cholesterol export from lysosomes. Read More

J Lipid Res 2019 Feb 1. Epub 2019 Feb 1.

University of Geneva, Switzerland;

In specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Read More

Eur J Pediatr 2019 Jan 28. Epub 2019 Jan 28.

Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte - CMIN, Centro Hospitalar Universitário do Porto, Largo da Maternidade de Júlio Dinis, 4050-651, Porto, Portugal.

Metabolic liver diseases (MLD) are an important group of disorders presenting with neonatal cholestasis (NC). The spectrum of liver involvement is wide and the presumptive diagnosis is traditionally based on clinical and laboratory findings. Recently, next-generation sequencing (NGS) panels have emerged as an appealing tool to diagnose neonatal/infantile cholestatic disorders. Read More

Eur J Nucl Med Mol Imaging 2019 Jan 28. Epub 2019 Jan 28.

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.

Purpose: Niemann-Pick type C (NPC) is a cholesterol storage disease characterized by disruption in the endosomal-lysosomal transport system that leads to the accumulation of cholesterol and glycolipids in lysosomes. Developmental cognitive delay and progressive motor and cognitive impairment are characteristic of the disease. Tau accumulation has been reported in some NPC patients. Read More

Cardiovasc Drugs Ther 2019 Jan 22. Epub 2019 Jan 22.

Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.

Purpose: Oxycholesterols (OCs) are produced from cholesterol by oxidation of the steroidal backbone and side-chain. OCs are present in blood and evidence suggests their involvement in disease development and progression. However, limited information is available regarding the absorption mechanisms and relative absorption rates of dietary OCs. Read More

Comp Biochem Physiol Part D Genomics Proteomics 2019 Mar 17;29:320-329. Epub 2019 Jan 17.

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China. Electronic address:

In arthropods, the large majority of studies on olfaction have been mainly focused on insects, whereas little on Arachnida, even though olfaction is very important in arachnid behavior. Pardosa pseudoannulata is one of the most common wandering spiders in rice fields, as the important natural enemy against a range of pests. However, little is known about the potential chemosensory proteins involved in olfactory behavior of these spiders. Read More

Front Immunol 2018 7;9:3089. Epub 2019 Jan 7.

Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.

Niemann-Pick type C1 (NPC1) disease is caused by a deleterious mutation in the gene, causing lysosomal accumulation of unesterified cholesterol and sphingolipids. Consequently, NPC1 disease patients suffer from severe neurovisceral symptoms which, in the absence of effective treatments, result in premature death. NPC1 disease patients display increased plasma levels of cholesterol oxidation products such as those enriched in oxidized low-density lipoprotein (oxLDL), a pro-inflammatory mediator. Read More

Orphanet J Rare Dis 2019 Jan 21;14(1):20. Epub 2019 Jan 21.

University of Pretoria, Pretoria, South Africa.

Background: Rare and ultra-rare diseases (URDs) are often chronic and life-threatening conditions that have a profound impact on sufferers and their families, but many are notoriously difficult to detect. Niemann-Pick disease type C (NP-C) serves to illustrate the challenges, benefits and pitfalls associated with screening for ultra-rare inborn errors of metabolism (IEMs). A comprehensive, non-systematic review of published information from NP-C screening studies was conducted, focusing on diagnostic methods and study designs that have been employed to date. Read More

Int J Mol Med 2019 Mar 15;43(3):1531-1541. Epub 2019 Jan 15.

Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

Dogs are a major source of indoor allergens. However, the prevalence of dog allergies in China remains unclear, especially in children. In the present study, Can f 7, a canine allergen belonging to the Niemann pick type C2 protein family, was selected to study its sensitization rate in Chinese children with dog allergies. Read More

Int J Mol Sci 2019 Jan 15;20(2). Epub 2019 Jan 15.

Rare Metabolic Diseases Unit, Pediatric Department, Fondazione MBBM, Università degli Studi di Milano Bicocca, San Gerardo Hospital, ASST di Monza, 20900 Monza, Italy.

Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main molecular pathways known so far to be involved in the pathogenesis of the disease. A literature search was conducted using the Medline/PubMed and EMBASE databases to identify studies, from 1968 through to November 2018, that investigated the respiratory manifestations and molecular pathways affected in LSD. Read More

ACS Infect Dis 2019 Jan 28. Epub 2019 Jan 28.

Center for Molecular Parasitology, Department of Microbiology and Immunology , Drexel University College of Medicine , 2900 Queen Lane , Philadelphia , Pennsylvania 19129 , United States of America.

Lipid homeostasis is essential to the maintenance of life. We previously reported that disruptions of the parasite Na homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na homeostasis. Read More

Neural Regen Res 2019 Apr;14(4):582-587

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. Read More

CNS Drugs 2019 Feb;33(2):125-142

Neuropsychiatry Unit, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. Read More

Nat Microbiol 2019 Mar 7;4(3):390-395. Epub 2019 Jan 7.

CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.

Filoviruses, especially Ebola virus (EBOV) and Marburg virus (MARV), are notoriously pathogenic and capable of causing severe haemorrhagic fever diseases in humans with high lethality. The risk of future outbreaks is exacerbated by the discovery of other bat-borne filoviruses of wide genetic diversity globally. Here we report the characterization of a phylogenetically distinct bat filovirus, named Měnglà virus (MLAV). Read More

Skelet Muscle 2019 Jan 5;9(1). Epub 2019 Jan 5.

Department of Cell Biology and Molecular Genetics, University of Maryland, 2134 Bioscience Research Building, College Park, MD, 20742-5815, USA.

Background: Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Read More

Am J Med Genet B Neuropsychiatr Genet 2019 Jan 16;180(1):46-54. Epub 2018 Dec 16.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Many genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with standard psychotropic medications. This study tests the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected inborn errors of metabolism (IEMs). Using next-generation sequencing, 2046 psychiatric patients were screened for pathogenic variants in genes associated with four IEMs, Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM), and acute intermittent porphyria (AIP). Read More

Clin Genet 2019 Mar 8;95(3):415-419. Epub 2019 Jan 8.

Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.

Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. Read More

Biomed Rep 2018 Dec 3;9(6):545. Epub 2018 Oct 3.

[This corrects the article DOI: 10.3892/br.2018. Read More

EMBO J 2019 Jan 7;38(2). Epub 2018 Dec 7.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain

Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann-Pick disease type A (NPA). Read More

Eur J Pharm Sci 2019 Feb 4;128:202-208. Epub 2018 Dec 4.

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address:

A new renaissance started in the research and application of cyclodextrins a few years ago. 2-Hydroxypropyl-beta-cyclodextrin (HPBCD) is used in the formulation of drugs and recently orphan designation was granted for the treatment of Niemann-Pick disease, type C. HPBCD is considered to be safe, but the exact mechanism of action and side effects are not completely explained. Read More

Nat Nanotechnol 2019 Feb 3;14(2):176-183. Epub 2018 Dec 3.

Department of Chemistry, The University of Chicago, Chicago, IL, USA.

Lysosomes are multifunctional, subcellular organelles with roles in plasma membrane repair, autophagy, pathogen degradation and nutrient sensing. Dysfunctional lysosomes underlie Alzheimer's disease, Parkinson's disease and rare lysosomal storage diseases, but their contributions to these pathophysiologies are unclear. Live imaging has revealed lysosome subpopulations with different physical characteristics including dynamics, morphology or cellular localization. Read More

Handb Exp Pharmacol 2018 Nov 27. Epub 2018 Nov 27.

Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.

Sphingosine, ceramide, sphingosine-1-phosphate, and other related sphingolipids have emerged as important bioactive molecules involved in a variety of key cellular processes such as cell growth, differentiation, apoptosis, exosome release, and inter- and intracellular cell communication, making the pathways of sphingolipid metabolism a key domain in maintaining cell homeostasis (Hannun and Obeid, Trends Biochem Sci 20:73-77, 1995; Hannun and Obeid, Nat Rev Mol Cell Biol 9:139-150, 2008; Kosaka et al., J Biol Chem 288:10849-10859, 2013). Various studies have determined that these pathways play a central role in regulating intracellular production of ceramide and the other bioactive sphingolipids and hence are an important component of signaling in various diseases such as cancer, diabetes, and neurodegenerative and cardiovascular diseases (Chaube et al. Read More

Int J Mol Sci 2018 Nov 14;19(11). Epub 2018 Nov 14.

Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.

Niemann⁻Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the or genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Read More

Exp Mol Med 2018 Nov 14;50(11):149. Epub 2018 Nov 14.

Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.

We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann-Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15-EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Read More

Int J Mol Sci 2018 Nov 12;19(11). Epub 2018 Nov 12.

Department of Anatomy, University of Rostock, 18057 Rostock, Germany.

Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. Read More

J Heart Lung Transplant 2019 Jan 16;38(1):100-101. Epub 2018 Oct 16.

Division of Pulmonary and Critical Care Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Mol Genet Metab 2018 Dec 30;125(4):345-350. Epub 2018 Oct 30.

Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA. Electronic address:

Niemann-Pick disease, type C1 (NPC1) is an inborn error of metabolism that results in endolysosomal accumulation of unesterified cholesterol. Clinically, NPC1 manifests as cholestatic liver disease in the newborn or as a progressive neurogenerative condition characterized by cerebellar ataxia and cognitive decline. Currently there are no FDA approved therapies for NPC1. Read More

J Cell Biochem 2019 Apr 2;120(4):6580-6588. Epub 2018 Nov 2.

Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.

Background: Niemann Pick type C (NPC) lysosomal disorder is linked to the disruption of cholesterol transport. Recent data suggest that the molecular background of this disease is more complex. It was found that accumulation of cholesterol and glycolipids in the late endosomal/lysosomal compartment of NPC1 cells may affect mitochondrial functions. Read More

Parkinsonism Relat Disord 2018 Oct 26. Epub 2018 Oct 26.

Division of Neurology, Department of Clinical Medicine, Universidade Federal do Ceará, Brazil; Neurology Service, Hospital Geral de Fortaleza, Fortaleza, Ceará, Brazil; Center of Health Sciences, Universidade Estadual do Ceará, Brazil. Electronic address:

Background: There are few studies reporting characteristics of patients with cerebellar ataxias in the Brazilian population. The aim of this study was to provide a detailed neurological description of patients with hereditary ataxia followed by a neurology outpatient service in Brazil.

Methods: Neurological and clinical evaluation of patients with hereditary ataxia was performed at a neurology service outpatient clinic of a hospital in Northeast Brazil between October 2013 and January 2015. Read More

Int J Mol Sci 2018 Nov 1;19(11). Epub 2018 Nov 1.

Departamento de Bioquímica, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, Apdo.644, 48080 Bilbao, Spain.

Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine and, intracellularly synthesized cholesterol that is mainly synthesized in the liver. Read More

Am J Physiol Lung Cell Mol Physiol 2019 Jan 25;316(1):L206-L215. Epub 2018 Oct 25.

Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

Pseudomonas aeruginosa secretes outer-membrane vesicles (OMVs) that fuse with cholesterol-rich lipid rafts in the apical membrane of airway epithelial cells and decrease wt-CFTR Cl secretion. Herein, we tested the hypothesis that a reduction of the cholesterol content of CF human airway epithelial cells by cyclodextrins reduces the inhibitory effect of OMVs on VX-809 (lumacaftor)-stimulated Phe508del CFTR Cl secretion. Primary CF bronchial epithelial cells and CFBE cells were treated with vehicle, hydroxypropyl-β-cyclodextrin (HPβCD), or methyl-β-cyclodextrin (MβCD), and the effects of OMVs secreted by P. Read More

Rev Colomb Psiquiatr 2018 Oct - Dec;47(4):244-251. Epub 2017 Jun 17.

Service Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Université de Nantes, Nantes, Francia.

Some diseases secondary to inborn errors of metabolism are associated with psychiatric disorders or minor neurological symptoms. The existence of some cases with exclusively psychiatric symptoms represents a diagnostic and therapeutic challenge. The aim of this article is to describe seven treatable neurometabolic disorders that should be taken into account in the psychiatric consultation as they manifest with psychiatric symptoms that mask the organic origin of the disorder. Read More

Orphanet J Rare Dis 2018 Oct 1;13(1):175. Epub 2018 Oct 1.

Reference Centre for Lysosomal Diseases (CRML), Department of Pediatric Neurology, and Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Hôpital Armand Trousseau, F-75012, Paris, France.

Background: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date.

Methods: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Read More

Cell Death Dis 2018 Oct 3;9(10):1019. Epub 2018 Oct 3.

Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN, 37208, USA.

Niemann-Pick type C (NPC) disease is a fatal hereditary neurodegenerative disorder characterized by a massive accumulation of cholesterol in lysosomes and late endosomes due to a defect in intracellular cholesterol trafficking. Dysfunction in intracellular cholesterol trafficking is responsible for about 50 rare inherited lysosomal storage disorders including NPC. The lysosomal proteins NPC1 and NPC2 play a crucial role in trafficking of cholesterol from late endosomes and lysosomes to other cellular compartments. Read More

Sci Transl Med 2018 Oct;10(461)

Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and drug-induced phospholipidosis. Current methods cannot monitor endolysosomal lipid content in vivo, hindering preclinical drug development and research into the mechanisms linking endolysosomal lipid accumulation to disease progression. We developed a single-walled carbon nanotube-based optical reporter that noninvasively measures endolysosomal lipid accumulation via bandgap modulation of its intrinsic near-infrared emission. Read More

J Lipid Res 2018 Dec 28;59(12):2446-2455. Epub 2018 Sep 28.

Department of Chemistry University of Illinois at Chicago, Chicago, IL 60607

Mass spectrometry imaging (MSI) is a tool to rapidly map the spatial location of analytes without the need for tagging or a reporter system. Niemann-Pick disease type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder characterized by accumulation of unesterified cholesterol and sphingolipids in the endo-lysosomal system. Here, we use MSI to visualize lipids including cholesterol in cerebellar brain tissue from the NPC1 symptomatic mouse model and unaffected controls. Read More

J Child Neurol 2018 Dec 28;33(14):882-887. Epub 2018 Sep 28.

2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Inherited leukodystrophies are a group of diseases affecting central nervous system myelin that lead to death or significant health problems. Although for most leukodystrophies there are no curative treatments, for a handful of diseases hematopoietic stem cell transplantation (HSCT; bone marrow transplant) can stop disease progression, and if initiated in a timely fashion, prevent many or all neurologic and other systems involvement. However, HSCT is a complex procedure with significant morbidity and mortality risks. Read More

Liver Int 2019 Mar 17;39(3):463-469. Epub 2018 Oct 17.

Department of Medical Microbiology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background & Aims: Despite high-risk behaviour, 10%-20% of HCV multiple exposed individuals remain uninfected (MEU), whilst the remainder become infected (MEI). We hypothesize that host factors play a role in HCV susceptibility. We aimed to identify polymorphisms in host genes that encode for proteins involved in viral entry: CD81, Scavenger receptor 1 (SR-1), Low-density lipoprotein receptor (LDL-R), Claudin-1 (CLDN1), Occludin (OCLN) and Niemann-Pick C1-like 1 (NPC1L1). Read More

Acta Neuropathol Commun 2018 Sep 24;6(1):98. Epub 2018 Sep 24.

Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, 60208, USA.

Niemann-Pick Type C1 (NPC1) disease is a fatal neurovisceral disorder caused by dysfunction of NPC1 protein, which plays a role in intracellular cholesterol trafficking. The cholesterol-chelating agent, 2-hydroxypropyl-β-cyclodextrin (HPβCD), is currently undergoing clinical trials for treatment of this disease. Though promising in alleviating neurological symptoms, HPβCD causes irreversible hearing loss in NPC1 patients and outer hair cell (OHC) death in animal models. Read More

J Lipid Res 2018 Nov 21;59(11):2181-2187. Epub 2018 Sep 21.

Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan

Intestinal cholesterol absorption is a key regulator of systemic cholesterol homeostasis. Excessive dietary cholesterol and its intestinal uptake lead to hypercholesterolemia, a major risk factor for cardiovascular disease. Intestinal cholesterol uptake is mediated by Niemann-Pick C1-like 1 (NPC1L1), a transmembrane protein localized in membrane microdomains (lipid rafts) enriched in gangliosides and cholesterol. Read More