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    The extending spectrum of NPC1-related human disorders: from Niemann-Pick C1 Disease to obesity.
    Endocr Rev 2018 Jan 9. Epub 2018 Jan 9.
    Department of Health research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
    The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes / lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, liver and lung failure, due to cholesterol infiltration. In humans, genome wide association studies (GWAS) and post-GWAS reports highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Read More

    Fourier Transform Infrared Microscopy Enables Guidance of Automated Mass Spectrometry Imaging to Predefined Tissue Morphologies.
    Sci Rep 2018 Jan 10;8(1):313. Epub 2018 Jan 10.
    Center for Applied Research in Applied Biomedical Mass Spectrometry (ABIMAS), Mannheim University of Applied Sciences, Paul-Wittsack Str. 10, 68163, Mannheim, Germany.
    Multimodal imaging combines complementary platforms for spatially resolved tissue analysis that are poised for application in life science and personalized medicine. Unlike established clinical in vivo multimodality imaging, automated workflows for in-depth multimodal molecular ex vivo tissue analysis that combine the speed and ease of spectroscopic imaging with molecular details provided by mass spectrometry imaging (MSI) are lagging behind. Here, we present an integrated approach that utilizes non-destructive Fourier transform infrared (FTIR) microscopy and matrix assisted laser desorption/ionization (MALDI) MSI for analysing single-slide tissue specimen. Read More

    Sub-cellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases.
    Nano Lett 2018 Jan 9. Epub 2018 Jan 9.
    We describe a new method to measure viscosity within sub-cellular organelles of a living cell using nanorheology. We demonstrate proof of concept by measuring viscosity in lysosomes in multiple cell types and disease models. The lysosome is an organelle, which is responsible for the breakdown of complex biomolecules. Read More

    Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol.
    Biol Pharm Bull 2018 ;41(1):1-10
    Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo.
    Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Read More

    Different effects of two mutations on the infectivity of Ebola virus glycoprotein in nine mammalian species.
    J Gen Virol 2018 Jan 4. Epub 2018 Jan 4.
    6​Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
    Ebola virus (EBOV), which belongs to the genus Ebolavirus, causes a severe and often fatal infection in primates, including humans, whereas Reston virus (RESTV) only causes lethal disease in non-human primates. Two amino acids (aa) at positions 82 and 544 of the EBOV glycoprotein (GP) are involved in determining viral infectivity. However, it remains unclear how these two aa residues affect the infectivity of Ebolavirus species in various hosts. Read More

    Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.
    Mol Genet Metab 2017 Dec 22. Epub 2017 Dec 22.
    Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:
    Background: In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders.

    Material And Methods: A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). Read More

    Inhibition of lysosomal Ca2+ signalling disrupts dendritic spine structure and impairs wound healing in neurons.
    Commun Integr Biol 2017 3;10(5-6):e1344802. Epub 2017 Nov 3.
    Department of Pharmacology, University of Oxford, Oxford, UK.
    A growing body of evidence suggests that lysosomes, which have traditionally been regarded as degradative organelles, can function as Ca2+ stores, regulated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). We previously demonstrated that in hippocampal pyramidal neurons, activity-dependent Ca2+ release from these stores triggers fusion of the lysosome with the plasma membrane. We found that the physiological role of this Ca2+-dependent fusion was to maintain the long-term structural enlargement of dendritic spines induced by synaptic activity. Read More

    Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr -/- mice.
    Sci Rep 2017 Dec 19;7(1):17845. Epub 2017 Dec 19.
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA.
    Atherosclerotic cardiovascular disease is a leading cause of death in the western world. Increased plasma triglyceride and cholesterol levels are major risk factors for this disease. Carboxylesterase 1 (Ces1/Ces1g) has been shown to play a role in metabolic control. Read More

    Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease.
    Front Physiol 2017 30;8:982. Epub 2017 Nov 30.
    Department of Cell Death and Proliferation, Intituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
    Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Read More

    Gait, Balance, and Coordination Impairments in Niemann Pick Disease, Type C1.
    J Child Neurol 2018 Jan;33(1):114-124
    2 Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
    This is the first study to objectively measure gait, balance, and upper limb coordination in a group of patients with NPC1 and compare the results to age and gender matched controls. This is also the first study to report effect sizes in these measures. Spatiotemporal gait analysis, static and dynamic posturography, and upper limb reaching motion analysis were performed. Read More

    Bis(monoacylglycero)phosphate lipids in the retinal pigment epithelium implicate lysosomal/endosomal dysfunction in a model of Stargardt disease and human retinas.
    Sci Rep 2017 Dec 11;7(1):17352. Epub 2017 Dec 11.
    Mass Spectrometry Research Center and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
    Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4 -/- Stargardt model mice compared to their relevant background strain. Read More

    Unravelling new pathways of sterol metabolism: lessons learned from in-born errors and cancer.
    Curr Opin Clin Nutr Metab Care 2017 Dec 13. Epub 2017 Dec 13.
    Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, UK.
    Purpose Of Review: To update researchers of recently discovered metabolites of cholesterol and of its precursors and to suggest relevant metabolic pathways.

    Recent Findings: Patients suffering from inborn errors of sterol biosynthesis, transport and metabolism display unusual metabolic pathways, which may be major routes in the diseased state but minor in the healthy individual. Although quantitatively minor, these pathways may still be important in healthy individuals. Read More

    In Niemann-Pick C1 mouse models, glial-only expression of the normal gene extends survival much further than do changes in genetic background or treatment with hydroxypropyl-beta-cyclodextrin.
    Gene 2018 Feb 6;643:117-123. Epub 2017 Dec 6.
    Department of Pediatrics, University of Arizona College of Medicine, Tucson, AZ 85724-5073, United States. Electronic address:
    The Npc1nmf164 allele of Npc1 provides a mouse model for Niemann-Pick disease type C1 (NPC1), a genetic disease known to have a widely variable phenotype. The transfer of the Npc1nmf164 mutation from the C57BL/6J inbred strain to the BALB/cJ inbred strain increased the mean lifespan from 117.8days to 153. Read More

    Characterization of an influenza virus pseudotyped with Ebolavirus glycoprotein.
    J Virol 2017 Dec 6. Epub 2017 Dec 6.
    Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom
    We have produced a new Ebola virus pseudotype: E-S-FLU, which can be handled in biosafety level-1/2 containment for laboratory analysis. E-S-FLU is a single cycle influenza virus coated with Ebolavirus glycoprotein, and it encodes enhanced green fluorescence protein as a reporter that replaces the influenza haemagglutinin. MDCK-SIAT1 cells were transduced to express Ebolavirus glycoprotein as a stable transmembrane protein for E-S-FLU production. Read More

    Intracellular Cholesterol Trafficking and Impact in Neurodegeneration.
    Front Mol Neurosci 2017 17;10:382. Epub 2017 Nov 17.
    Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
    Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. Read More

    Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients.
    Int J Dev Neurosci 2017 Nov 29;66:18-23. Epub 2017 Nov 29.
    Departamento de Análises, Faculdade de Farmácia, UFRGS, Avenida Ipiranga, 2752, CEP 90610-000, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas, Bioquímica, UFRGS, Rua Ramiro Barcelos, 2600, CEP 90035-003, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Av. Ipiranga, 2752, CEP 90610-000, Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, Rua Ramiro Barcelos, 2350, CEP 90035-003, Porto Alegre, RS, Brazil. Electronic address:
    Background: Niemann-Pick type C (NP-C), one of 50 inherited lysosomal storage disorders, is caused by NPC protein impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. The clinical manifestations of NP-C include hepatosplenomegaly, neurological and psychiatric symptoms. Current diagnosis for NP-C is based on observation of the accumulated cholesterol in fibroblasts of affected individuals, using an invasive and time expensive test, called Filipin staining. Read More

    Oculomotor abnormalities in children with Niemann-Pick type C.
    Mol Genet Metab 2017 Nov 16. Epub 2017 Nov 16.
    The University of Birmingham, School of Psychology, United Kingdom.
    Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. Read More

    Retro-2 and its dihydroquinazolinone derivatives inhibit filovirus infection.
    Antiviral Res 2018 Jan 22;149:154-163. Epub 2017 Nov 22.
    Texas Biomedical Research Institute, San Antonio, TX, USA. Electronic address:
    Members of the family Filoviridae cause severe, often fatal disease in humans, for which there are no approved vaccines and only a few experimental drugs tested in animal models. Retro-2, a small molecule that inhibits retrograde trafficking of bacterial and plant toxins inside host cells, has been demonstrated to be effective against a range of bacterial and virus pathogens, both in vitro and in animal models. Here, we demonstrated that Retro-2 and its derivatives, Retro-2. Read More

    Cyclodextrins and Iatrogenic Hearing Loss: New Drugs with Significant Risk.
    Front Cell Neurosci 2017 8;11:355. Epub 2017 Nov 8.
    Department of Otolaryngology-Head & Neck Surgery, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, United States.
    Cyclodextrins are a family of cyclic oligosaccharides with widespread usage in medicine, industry and basic sciences owing to their ability to solubilize and stabilize guest compounds. In medicine, cyclodextrins primarily act as a complexing vehicle and consequently serve as powerful drug delivery agents. Recently, uncomplexed cyclodextrins have emerged as potent therapeutic compounds in their own right, based on their ability to sequester and mobilize cellular lipids. Read More

    L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease.
    Sci Rep 2017 Nov 21;7(1):15944. Epub 2017 Nov 21.
    Advanced Clinical Research Center, Institute for Neurological Disorders, Kawasaki, Japan.
    Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (-/-). Under serum-starved conditions, NPC (-/-) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Read More

    Generation of patient specific human neural stem cells from Niemann-Pick disease type C patient-derived fibroblasts.
    Oncotarget 2017 Oct 7;8(49):85428-85441. Epub 2017 Aug 7.
    Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.
    Niemann-Pick disease type C (NPC) is a neurodegenerative and lysosomal lipid storage disorder, characterized by the abnormal accumulation of unesterified cholesterol and glycolipids, which is caused by mutations in the NPC1 genes. Here, we report the generation of human induced neural stem cells from NPC patient-derived fibroblasts (NPC-iNSCs) using only two reprogramming factors SOX2 and HMGA2 without going through the pluripotent state. NPC-iNSCs were stably expandable and differentiated into neurons, astrocytes, and oligodendrocytes. Read More

    Lysosomal storage diseases.
    Transl Sci Rare Dis 2017 May 25;2(1-2):1-71. Epub 2017 May 25.
    Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
    Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Read More

    Polyrotaxane-based systemic delivery of β-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease.
    J Control Release 2018 Jan 11;269:148-158. Epub 2017 Nov 11.
    Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan. Electronic address:
    Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl β-cyclodextrin (HP-β-CD) promotes the excretion of cholesterol and prolongs the life span in animal models of NPC disease, it requires extremely high dose. We developed acid-labile β-CD-based polyrotaxanes (PRXs) comprising multiple β-CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of β-CD in NPC disease. Read More

    [From the Hallervorden-Spatz eponym to the molecular terminology].
    Orv Hetil 2017 Oct;158(43):1723-1727
    Patológiai Osztály, Markusovszky Egyetemi Oktatókórház Szombathely, Markusovszky u. 5., 9700.
    Introduction And Aim: A combination of Niemann-Pick- and Hallervorden-Spatz diseases led to the death of a 17-year-old boy in 1994. Genetic counseling necessitated further investigations in 2017. Meanwhile, the nomenclature of Hallervorden-Spatz disease has been abandoned. Read More


    Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases.
    Wellcome Open Res 2017 31;2:75. Epub 2017 Aug 31.
    Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK.
    In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Read More

    Hematopoietic stem cell transplantation in Niemann-Pick disease type B monitored by chitotriosidase activity.
    Pediatr Blood Cancer 2018 Feb 1;65(2). Epub 2017 Nov 1.
    Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Torino, Italy.
    Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness. Read More

    Corrigendum to "Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child".
    Case Rep Pediatr 2017 20;2017:4120361. Epub 2017 Sep 20.
    Sanin Rosai Hospital, 1-8-1 Kaike Shinden, Yonago, Tottori 683-8605, Japan.
    [This corrects the article DOI: 10.1155/2015/807591.]. Read More

    The adenosine A2A receptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease.
    Neurobiol Dis 2018 Feb 25;110:1-11. Epub 2017 Oct 25.
    National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
    Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2A receptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Read More

    Alteration of cortical excitability and its modulation by Miglustat in Niemann-Pick disease type C.
    J Clin Neurosci 2018 Jan 23;47:214-217. Epub 2017 Oct 23.
    Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. Electronic address:
    Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Read More

    Hydroxypropyl-β-cyclodextrin formulated in nasal chitosan microspheres as candidate therapeutic agent in Alzheimer's disease.
    Curr Drug Deliv 2017 Oct 19. Epub 2017 Oct 19.
    University of Sassari, Department of Chemistry and Pharmacy, via Muroni 23/a, 07100 Sassari. Italy.
    Hydroxypropyl-β-cyclodextrin (HP-CD) is a hydroxyalkyl derivative of native β-cyclodextrin, cyclic oligosaccharide able to form inclusion complexes with many drugs and biomolecules [1]. Cyclodextrins have a possible neuroprotective effect due to their capability to extract and deplete cholesterol from cell membranes [1]. HP-CD is classified as an excipient (cyclodextrins are in fact widely used to improve solubility of poorly water soluble drugs) and it is not been FDA-approved as therapeutic agent. Read More

    2-hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier: Considerations for Niemann-Pick Disease Type C1.
    Curr Pharm Des 2017 Oct 19. Epub 2017 Oct 19.
    Educational Trainers and Consultants 39 Swains Pond Ave Melrose, MA 02176. United States.
    The rare, chronic, autosomal-recessive lysosomal storage disease Niemann-Pick disease type C1 (NPC1) is characterized by progressively debilitating and ultimately fatal neurological manifestations. There is tremendous need for disease-modifying therapies that address NPC1 neurological pathophysiology, and passage through the blood-brain barrier represents an important consideration for novel NPC1 drugs. Animal investigations of 2-hydroxypropyl--cyclodextrins (HPCD) in NPC1 in mice demonstrated that HPCD does not cross the blood-brain barrier in significant amounts but suggested a potential for these complex oligosaccharides to moderately impact CNS manifestations when administered subcutaneously or intraperitoneally at very high doses; however, safety concerns regarding pulmonary toxicity were raised. Read More

    Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C.
    Wellcome Open Res 2017 31;2:76. Epub 2017 Aug 31.
    Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK.
    Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. Read More

    Neurite Outgrowth Inhibitor B Receptor: A Versatile Receptor with Multiple Functions and Actions.
    DNA Cell Biol 2017 Dec 23;36(12):1142-1150. Epub 2017 Oct 23.
    Department of Histology and Embryology, Clinical Anatomy and Reproductive Medicine Application Institute, University of South China , Hengyang, China .
    Members of the reticulon protein family are predominantly distributed within the endoplasmic reticulum. The neurite outgrowth inhibitor (Nogo) has three subtypes, including Nogo-A (200 kDa), Nogo-B (55 kDa), and Nogo-C (25 kDa). Nogo-A and Nogo-C are potent Nogos that are predominantly expressed in the central nervous system. Read More

    Aberrant activation of Cdc2/cyclin B1 is involved in initiation of cytoskeletal pathology in murine Niemann-Pick disease type C.
    J Huazhong Univ Sci Technolog Med Sci 2017 Oct 20;37(5):732-739. Epub 2017 Oct 20.
    Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
    Niemann-Pick disease type C (NPC) is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary tangles (NFTs) formation, and axonal spheroids (AS). Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC (npc mice). With a goal of elucidating the mechanisms underlying the lesion formation, we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2, cdk4, and cdk5 in lesion formation in young npc mice. Read More

    The Effects of Extracellular Serum Concentration on APP Processing in Npc1-Deficient APP-Overexpressing N2a Cells.
    Mol Neurobiol 2017 Oct 19. Epub 2017 Oct 19.
    Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, T6G 2M8, Canada.
    Amyloid precursor protein (APP) is cleaved by a set of proteases including α-/β-/γ- and recently identified η-secretases, generating C-terminal fragments (CTFs) of varying lengths and amyloid β (Aβ) peptides, which are considered to play a pivotal role in Alzheimer's disease (AD) pathogenesis. Cellular cholesterol content/distribution can regulate the production/clearance of APP metabolites and hence modify AD pathology. To determine the functional relation between endosomal-lysosomal (EL) cholesterol sequestration and APP metabolism, we used our recently developed mouse N2a-ANPC cells that overexpress Swedish mutant human APP in the absence of cholesterol-trafficking Niemann-Pick type C1 (Npc1) protein. Read More

    Cognitive impairment profile in adult patients with Niemann pick type C disease.
    Orphanet J Rare Dis 2017 Oct 18;12(1):166. Epub 2017 Oct 18.
    Neurology Department, Reference Center for Lysosomal Diseases, Hospital of Pitié-Salpêtrière, Paris, France.
    Background: Cognitive impairment is one of the core symptoms of Niemann Pick type C (NPC) disease, but few data concerning the neuropsychological profile of NPC patients are available. The aim of our study was to characterize cognitive impairments in NPC disease and to assess the evolution of these symptoms and the impact of miglustat on cognitive follow-up.

    Methods: We conducted a retrospective study of 21 adult patients diagnosed with NPC disease. Read More

    Hepatitis C Virus Replication Depends on Endosomal Cholesterol Homeostasis.
    J Virol 2018 Jan 14;92(1). Epub 2017 Dec 14.
    Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
    Similar to other positive-strand RNA viruses, hepatitis C virus (HCV) causes massive rearrangements of intracellular membranes, resulting in a membranous web (MW) composed of predominantly double-membrane vesicles (DMVs), the presumed sites of RNA replication. DMVs are enriched for cholesterol, but mechanistic details on the source and recruitment of cholesterol to the viral replication organelle are only partially known. Here we focused on selected lipid transfer proteins implicated in direct lipid transfer at various endoplasmic reticulum (ER)-membrane contact sites. Read More

    Microglial involvement in the development of olfactory dysfunction.
    J Vet Sci 2017 Oct 13. Epub 2017 Oct 13.
    Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
    Olfaction is one of the oldest and important senses for life. Olfactory impairment is the most common clinical manifestation among elderly, and its prevalence is sharply increased with aging. Importantly, growing evidence has shown that olfactory dysfunction is the first sign of neurodegeneration, indicating the importance of olfactory assessment as an early diagnostic marker for the detection of neurological disorders. Read More

    Chemosensing of honeybee parasite, Varroa destructor: Transcriptomic analysis.
    Sci Rep 2017 Oct 12;7(1):13091. Epub 2017 Oct 12.
    Institute of Plant Protection, Agricultural Research Organization, The Volcani Center, Rishon LeZion, Israel.
    Chemosensing is a primary sense in nature, however little is known about its mechanism in Chelicerata. As a model organism we used the mite Varroa destructor, a key parasite of honeybees. Here we describe a transcriptomic analysis of two physiological stages for the Varroa foreleg, the site of primary olfactory organ. Read More

    The ceramide activated protein phosphatase Sit4 impairs sphingolipid dynamics, mitochondrial function and lifespan in a yeast model of Niemann-Pick type C1.
    Biochim Biophys Acta 2018 Jan 6;1864(1):79-88. Epub 2017 Oct 6.
    Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. Electronic address:
    The Niemann-Pick type C is a rare neurodegenerative disease that results from loss-of-function point mutations in NPC1 or NPC2, which affect the homeostasis of sphingolipids and sterols in human cells. We have previously shown that yeast lacking Ncr1, the orthologue of human NPC1 protein, display a premature ageing phenotype and higher sensitivity to oxidative stress associated with mitochondrial dysfunctions and accumulation of long chain bases. In this study, a lipidomic analysis revealed specific changes in the levels of ceramide species in ncr1Δ cells, including decreases in dihydroceramides and increases in phytoceramides. Read More

    Niemann-Pick disease type C in the newborn period: a single-center experience.
    Eur J Pediatr 2017 Dec 27;176(12):1669-1676. Epub 2017 Sep 27.
    Department of Pediatric Gastroenterology, Hacettepe University Children's Hospital, Sihhiye, 06100, Ankara, Turkey.
    Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder with a great variation in clinical spectrum and age at presentation. Clinical features of 10 NPC patients who presented in the newborn period between 1993 and 2015 at our center were retrospectively analyzed. Males and females were equally distributed; there was a history of parental consanguinity (n = 8) and first-degree relative with NPC (n = 3). Read More

    Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1.
    Diseases 2016 Sep 8;4(3). Epub 2016 Sep 8.
    National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
    Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI) of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. Read More

    Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.
    Cancer Lett 2017 Nov 18;409:91-103. Epub 2017 Sep 18.
    Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:
    Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Read More

    The role of epigenetics in lysosomal storage disorders: Uncharted territory.
    Mol Genet Metab 2017 Nov 1;122(3):10-18. Epub 2017 Aug 1.
    Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, United States.
    The study of the contribution of epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, to human disease has enhanced our understanding of different cellular processes and diseased states, as well as the effect of environmental factors on phenotypic outcomes. Epigenetic studies may be particularly relevant in evaluating the clinical heterogeneity observed in monogenic disorders. The lysosomal storage disorders are Mendelian disorders characterized by a wide spectrum of associated phenotypes, ranging from neonatal presentations to symptoms that develop in late adulthood. Read More

    Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry.
    World J Biol Psychiatry 2017 Oct 9:1-10. Epub 2017 Oct 9.
    h Pediatric and Adolescent Medicine , Mayo Clinic , Rochester , MN , USA.
    Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry.

    Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Read More

    Exacerbating and reversing lysosomal storage diseases: from yeast to humans.
    Microb Cell 2017 Aug 25;4(9):278-293. Epub 2017 Aug 25.
    Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032.
    Lysosomal storage diseases (LSDs) arise from monogenic deficiencies in lysosomal proteins and pathways and are characterized by a tissue-wide accumulation of a vast variety of macromolecules, normally specific to each genetic lesion. Strategies for treatment of LSDs commonly depend on reduction of the offending metabolite(s) by substrate depletion or enzyme replacement. However, at least 44 of the ~50 LSDs are currently recalcitrant to intervention. Read More

    Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.
    Cell Rep 2017 Sep;20(11):2565-2574
    Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
    Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Read More

    A Carbon Nanotube Optical Reporter Maps Endolysosomal Lipid Flux.
    ACS Nano 2017 Nov 12;11(11):10689-10703. Epub 2017 Sep 12.
    Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
    Lipid accumulation within the lumen of endolysosomal vesicles is observed in various pathologies including atherosclerosis, liver disease, neurological disorders, lysosomal storage disorders, and cancer. Current methods cannot measure lipid flux specifically within the lysosomal lumen of live cells. We developed an optical reporter, composed of a photoluminescent carbon nanotube of a single chirality, that responds to lipid accumulation via modulation of the nanotube's optical band gap. Read More

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