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Glucocerebrosidase

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https://www.readbyqxmd.com/read/28319420/modelling-long-term-evolution-of-chitotriosidase-in-non-neuronopathic-gaucher-disease
#1
Cristina Drugan, Tudor C Drugan, Paula Grigorescu-Sido, Ioana Naşcu
Chitotriosidase, an enzyme secreted by activated macrophages, is widely used as a biomarker for therapeutic monitoring and patient follow-up in Gaucher disease (GD), a lysosomal disorder caused by an inherited deficiency of glucocerebrosidase. We analyzed the long-term evolution of chitotriosidase aiming to establish an accurate model that describes the influence of enzyme replacement therapy (ERT) and the impact of several covariates. A total of 55 patients with non-neuronopathic (type 1) GD were followed for almost 17 years (during a maximum of 7...
March 20, 2017: Scandinavian Journal of Clinical and Laboratory Investigation
https://www.readbyqxmd.com/read/28295625/oral-ambroxol-increases-brain-glucocerebrosidase-activity-in-a-nonhuman-primate
#2
Anna Migdalska-Richards, Wai Kin D Ko, Qin Li, Erwan Bezard, Anthony H V Schapira
Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood-brain barrier, increase GCase activity and reduce alpha-synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase activity in healthy nonhuman primates. We show that daily administration of ambroxol results in increased brain GCase activity...
March 12, 2017: Synapse
https://www.readbyqxmd.com/read/28286087/minos-insertion-mutant-of-the-drosophila-gba-gene-homologue-showed-abnormal-phenotypes-of-climbing-ability-sleep-and-life-span-with-accumulation-of-hydroxy-glucocerebroside
#3
Haruhisa Kawasaki, Takahiro Suzuki, Kumpei Ito, Tsubasa Takahara, Naoko Goto-Inoue, Mitsutoshi Setou, Kazuki Sakata, Norio Ishida
Gaucher's disease in humans is considered a deficiency of glucocerebrosidase (GlcCerase) that result in the accumulation of its substrate, glucocerebroside (GlcCer). Although mouse models of Gaucher's disease have been reported from several laboratories, these models are limited due to the perinatal lethality of GlcCerase gene. Here, we examined phenotypes of Drosophila melanogaster homologues genes of the human Gaucher's disease gene by using Minos insertion. One of two Minos insertion mutants to unknown function gene (CG31414) accumulates the hydroxy-GlcCer in whole body of Drosophila melanogaster...
March 7, 2017: Gene
https://www.readbyqxmd.com/read/28263001/assessment-of-bone-health-in-patients-with-type-1-gaucher-disease-using-impact-microindentation
#4
Sabina Herrera, Jordi Pérez-López, Marc Moltó-Abad, Roberto Güerri-Fernández, Elena Cabezudo, Silvana Novelli, Jordi Esteve, Albert Hernández, Inmaculada Roig, Xavier Solanich, Daniel Prieto-Alhambra, Xavier Nogués, Adolfo Díez-Pérez
BACKGROUND: Gaucher disease (GD), one of the commonest lysosomal disorders (a global population incidence of 1:50,000), is characterized by beta-glucocerebrosidase deficiency. Some studies have demonstrated bone infiltration in up to 80% of patients, even if asymptomatic. Bone disorder remains the main cause of morbidity in these patients, along with osteoporosis, avascular necrosis, and bone infarcts. Enzyme replacement therapy (ERT) has been shown to improve these symptoms. METHODS: This cross-sectional study included patients with type 1 Gaucher disease (GD1) selected from the Catalan Study Group on GD...
March 6, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28242245/inhibition-of-neuronal-mitochondrial-complex-i-or-lysosomal-glucocerebrosidase-is-associated-with-increased-dopamine-and-serotonin-turnover
#5
Carmen de la Fuente, Derek Burke, Simon Eaton, Simon J Heales
Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE)...
February 24, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28231462/the-complicated-relationship-between-gaucher-disease-and-parkinsonism-insights-from-a-rare-disease
#6
REVIEW
Elma Aflaki, Wendy Westbroek, Ellen Sidransky
The discovery of a link between mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, and the synucleinopathies directly resulted from the clinical recognition of patients with Gaucher disease with parkinsonism. Mutations in GBA1 are now the most common known genetic risk factor for several Lewy body disorders, and an inverse relationship exists between levels of glucocerebrosidase and oligomeric α-synuclein. While the underlying mechanisms are still debated, this complicated association is shedding light on the role of lysosomes in neurodegenerative disorders, demonstrating how insights from a rare disorder can direct research into the pathogenesis and therapy of seemingly unrelated common diseases...
February 22, 2017: Neuron
https://www.readbyqxmd.com/read/28225753/complement-drives-glucosylceramide-accumulation-and-tissue-inflammation-in-gaucher-disease
#7
Manoj K Pandey, Thomas A Burrow, Reena Rani, Lisa J Martin, David Witte, Kenneth D Setchell, Mary A Mckay, Albert F Magnusen, Wujuan Zhang, Benjamin Liou, Jörg Köhl, Gregory A Grabowski
Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease...
February 22, 2017: Nature
https://www.readbyqxmd.com/read/28223512/glucosylceramide-synthase-inhibition-alleviates-aberrations-in-synucleinopathy-models
#8
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba(D409V/D409V) and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28218669/a-review-of-gaucher-disease-pathophysiology-clinical-presentation-and-treatments
#9
REVIEW
Jérôme Stirnemann, Nadia Belmatoug, Fabrice Camou, Christine Serratrice, Roseline Froissart, Catherine Caillaud, Thierry Levade, Leonardo Astudillo, Jacques Serratrice, Anaïs Brassier, Christian Rose, Thierry Billette de Villemeur, Marc G Berger
Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells...
February 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28216145/a-human-neural-crest-stem-cell-derived-dopaminergic-neuronal-model-recapitulates-biochemical-abnormalities-in-gba1-mutation-carriers
#10
Shi-Yu Yang, Michelle Beavan, Kai-Yin Chau, Jan-Willem Taanman, Anthony H V Schapira
Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28212433/elevated-gm3-plasma-concentration-in-idiopathic-parkinson-s-disease-a-lipidomic-analysis
#11
Robin B Chan, Adler J Perotte, Bowen Zhou, Christopher Liong, Evan J Shorr, Karen S Marder, Un J Kang, Cheryl H Waters, Oren A Levy, Yimeng Xu, Hong Bin Shim, Itsik Pe'er, Gilbert Di Paolo, Roy N Alcalay
Parkinson's disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the 'Spot' study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols...
2017: PloS One
https://www.readbyqxmd.com/read/28207759/investigations-on-therapeutic-glucocerebrosidases-through-paired-detection-with-fluorescent-activity-based-probes
#12
Wouter W Kallemeijn, Saskia Scheij, Sascha Hoogendoorn, Martin D Witte, Daniela Herrera Moro Chao, Cindy P A A van Roomen, Roelof Ottenhoff, Herman S Overkleeft, Rolf G Boot, Johannes M F G Aerts
Deficiency of glucocerebrosidase (GBA) causes Gaucher disease (GD). In the common non-neuronopathic GD type I variant, glucosylceramide accumulates primarily in the lysosomes of visceral macrophages. Supplementing storage cells with lacking enzyme is accomplished via chronic intravenous administration of recombinant GBA containing mannose-terminated N-linked glycans, mediating the selective uptake by macrophages expressing mannose-binding lectin(s). Two recombinant GBA preparations with distinct N-linked glycans are registered in Europe for treatment of type I GD: imiglucerase (Genzyme), contains predominantly Man(3) glycans, and velaglucerase (Shire PLC) Man(9) glycans...
2017: PloS One
https://www.readbyqxmd.com/read/28193887/tmem175-deficiency-impairs-lysosomal-and-mitochondrial-function-and-increases-%C3%AE-synuclein-aggregation
#13
Sarah Jinn, Robert E Drolet, Paige E Cramer, Andus Hon-Kit Wong, Dawn M Toolan, Cheryl A Gretzula, Bhavya Voleti, Galya Vassileva, Jyoti Disa, Marija Tadin-Strapps, David J Stone
Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K(+) channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease...
February 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28171725/fluorinated-chaperone-%C3%AE-cyclodextrin-formulations-for-%C3%AE-glucocerebrosidase-activity-enhancement-in-neuronopathic-gaucher-disease
#14
M Isabel García-Moreno, Mario de la Mata, Elena M Sánchez-Fernández, Juan M Benito, Antonio Díaz-Quintana, Santos Fustero, Eiji Nanba, Katsumi Higaki, José A Sánchez-Alcázar, José M García Fernández, Carmen Ortiz Mellet
Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane skeleton based on 1,6-anhydro-l-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β-glucocerebrosidase mutants associated with the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts...
February 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28166796/coenzyme-q10-partially-restores-pathological-alterations-in-a-macrophage-model-of-gaucher-disease
#15
Mario de la Mata, David Cotán, Manuel Oropesa-Ávila, Marina Villanueva-Paz, Isabel de Lavera, Mónica Álvarez-Córdoba, Raquel Luzón-Hidalgo, Juan M Suárez-Rivero, Gustavo Tiscornia, José A Sánchez-Alcázar
BACKGROUND: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease...
February 6, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28144704/gaucher-disease-in-the-liver-on-hepatocyte-specific-contrast-agent-enhanced-mr-imaging
#16
Rama S Ayyala, Lisa A Teot, Jeanette M Perez Rossello
Gaucher disease is a hereditary lipid storage disorder that affects the enzyme beta glucocerebrosidase, causing accumulation of glucocerebroside in macrophages of the reticuloendothelial system. Accumulation can occur in the liver and spleen, manifesting as hepatosplenomegaly, as well as within the bone marrow. Hepatic involvement is usually diffuse but can occasionally manifest as focal liver lesions. We present a case of a 2-year-old boy with Gaucher disease and an infiltrating liver lesion detected on imaging, which was pathologically shown to be focal changes related to the disease...
February 1, 2017: Pediatric Radiology
https://www.readbyqxmd.com/read/28141506/antiviral-activity-of-acid-beta-glucosidase-1-on-enterovirus-71-a-causative-agent-of-hand-foot-mouth-disease
#17
Keiko Nakata, Satoshi Takeda, Atsushi Tanaka, Jimmy Kwang, Jun Komano
Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease (HFMD). EV71 causes fever, rash, diarrhea, and, in some cases, acute encephalopathy/encephalitis, which can be fatal. No specific treatment is currently available for EV71 infection. Here, we conducted a cDNA library screen and identified acid β-glucosidase 1 (GBA1; also known as β-glucocerebrosidase) as an EV71 resistance factor. The anti-EV71 function of GBA1 was verified by gene transduction and knockdown experiments. Cerezyme, a molecular drug used to treat Gaucher's disease having recombinant human GBA1 as the active ingredient, protected against EV71 infection...
January 27, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28130586/gene-therapy-approaches-in-the-non-human-primate-model-of-parkinson-s-disease
#18
REVIEW
D Pignataro, D Sucunza, A J Rico, I G Dopeso-Reyes, E Roda, A I Rodríguez-Perez, J L Labandeira-Garcia, V Broccoli, S Kato, K Kobayashi, José L Lanciego
The field of gene therapy has recently witnessed a number of major conceptual changes. Besides the traditional thinking that comprises the use of viral vectors for the delivery of a given therapeutic gene, a number of original approaches have been recently envisaged, focused on using vectors carrying genes to further modify basal ganglia circuits of interest. It is expected that these approaches will ultimately induce a therapeutic potential being sustained by gene-induced changes in brain circuits. Among others, at present, it is technically feasible to use viral vectors to (1) achieve a controlled release of neurotrophic factors, (2) conduct either a transient or permanent silencing of any given basal ganglia circuit of interest, (3) perform an in vivo cellular reprogramming by promoting the conversion of resident cells into dopaminergic-like neurons, and (4) improving levodopa efficacy over time by targeting aromatic L-amino acid decarboxylase...
January 27, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28126847/lipids-regulate-the-hydrolysis-of-membrane-bound-glucosylceramide-by-lysosomal-%C3%AE-glucocerebrosidase-gba1
#19
Misbaudeen Abdul-Hammed, Bernadette Breiden, Günter Schwarzmann, Konrad Sandhoff
Glucosylceramide is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B and C. The regulatory roles of lipids on the hydrolysis of membrane bound glucosylceramide by glucocerebrosidase GBA1 was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of Sap C. However, anionic lipids stimulate glucosylceramide hydrolysis at low pH by up to 1000 fold depending on the nature and position of the negative charges in their head groups while cationic lipids inhibit the degradation, thus showing the importance of electrostatic interactions between the polycationic GBA1 and the negatively charged vesicle surfaces at low pH...
January 26, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28123414/chaperoning-glucocerebrosidase-a-therapeutic-strategy-for-both-gaucher-disease-and-parkinsonism
#20
Benjamin McMahon, Elma Aflaki, Ellen Sidransky
No abstract text is available yet for this article.
November 2016: Neural Regeneration Research
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