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https://www.readbyqxmd.com/read/28218669/a-review-of-gaucher-disease-pathophysiology-clinical-presentation-and-treatments
#1
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
#2
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...
February 15, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28212433/elevated-gm3-plasma-concentration-in-idiopathic-parkinson-s-disease-a-lipidomic-analysis
#3
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
#4
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
#5
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 13, 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
#6
M Isabel Garcia-Moreno, Mario de la Mata, Elena Matilde Sánchez-Fernández, Juan M Benito, Antonio J Díaz-Quintana, Santos Fustero, Eiji Nanba, Katsumi Higaki, José A Sánchez Alcázar, José Manuel García Fernández, Carmen Ortiz Mellet
Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane 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 to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts...
February 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28166796/coenzyme-q10-partially-restores-pathological-alterations-in-a-macrophage-model-of-gaucher-disease
#7
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
#8
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
#9
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
#10
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
#11
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
#12
Benjamin McMahon, Elma Aflaki, Ellen Sidransky
No abstract text is available yet for this article.
November 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/28118713/production-of-rare-phyto-ceramides-from-abundant-food-plant-residues
#13
Mathias Reisberg, Norbert Arnold, Andrea Porzel, Reinhard H H Neubert, Birgit Dräger
Ceramides (Cers) are major components of the outermost layer of the skin, the stratum corneum, and play a crucial role in permeability barrier functions. Alterations in Cer composition causing skin diseases are compensated with semisynthetic skin-identical Cers. Plants constitute new resources for Cer production as they contain glucosylceramides (GluCers) as major components. GluCers were purified from industrial waste plant materials, apple pomace (Malus domestica), wheat germs (Triticum sp.), and coffee grounds (Coffea sp...
February 13, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28103924/combination-therapy-in-a-patient-with-chronic-neuronopathic-gaucher-disease-a-case-report
#14
Ferdinando Ceravolo, Michele Grisolia, Simona Sestito, Francesca Falvo, Maria Teresa Moricca, Daniela Concolino
BACKGROUND: The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations...
January 20, 2017: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/28098793/osteocyte-alterations-induce-osteoclastogenesis-in-an-in-vitro-model-of-gaucher-disease
#15
Constanza Bondar, Maximiliano Ormazabal, Andrea Crivaro, Malena Ferreyra-Compagnucci, María Victoria Delpino, Paula Adriana Rozenfeld, Juan Marcos Mucci
Gaucher disease (GD) is caused by mutations in the glucosylceramidase β (GBA 1) gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to the accumulation of the glycolipid glucocerebroside in the lysosomes of cells, mainly in the monocyte/macrophage lineage. Its mildest form is Type I GD, characterized by non-neuronopathic involvement. Bone compromise is the most disabling aspect of the Gaucher disease. However, the pathophysiological aspects of skeletal alterations are not yet fully understood...
January 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28098348/impact-of-lysosomal-storage-disorders-on-biology-of-mesenchymal-stem-cells-evidences-from-in-vitro-silencing-of-glucocerebrosidase-gba-and-alpha-galactosidase-a-gla-enzymes
#16
Tiziana Squillaro, Antonucci Ivana, Nicola Alessio, Anna Esposito, Marilena Cipollaro, Marina Melone, Gianfranco Peluso, Liborio Stuppia, Umberto Galderisi
Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues...
January 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28090684/predict-pd-an-online-approach-to-prospectively-identify-risk-indicators-of-parkinson-s-disease
#17
Alastair J Noyce, Lea R'Bibo, Luisa Peress, Jonathan P Bestwick, Kerala L Adams-Carr, Niccolo E Mencacci, Christopher H Hawkes, Joseph M Masters, Nicholas Wood, John Hardy, Gavin Giovannoni, Andrew J Lees, Anette Schrag
BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD). OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations...
February 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28030538/gba-variants-influence-motor-and-non-motor-features-of-parkinson-s-disease
#18
Silvia Jesús, Ismael Huertas, Inmaculada Bernal-Bernal, Marta Bonilla-Toribio, María Teresa Cáceres-Redondo, Laura Vargas-González, Myriam Gómez-Llamas, Fátima Carrillo, Enrique Calderón, Manuel Carballo, Pilar Gómez-Garre, Pablo Mir
The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression...
2016: PloS One
https://www.readbyqxmd.com/read/28011901/efferocytosis-is-impaired-in-gaucher-macrophages
#19
Elma Aflaki, Daniel K Borger, Richard J Grey, Martha Kirby, Stacie Anderson, Grisel Lopez, Ellen Sidransky
Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylceramide-laden macrophages resulting from impaired digestion of aged erythrocytes or apoptotic leukocytes. Studies of macrophages from patients with type 1 Gaucher disease with genotypes N370S/N370S, N370S/L444P or N370S/c.84dupG revealed that Gaucher macrophages have impaired efferocytosis resulting from reduced levels of p67phox and Rab7. The decreased Rab7 expression leads to impaired fusion of phagosomes with lysosomes...
December 23, 2016: Haematologica
https://www.readbyqxmd.com/read/27981207/dataset-of-total-oligomeric-alpha-synuclein-and-hemoglobin-levels-in-plasma-in-parkinson-s-disease
#20
A Emelyanov, P Andoskin, S Pchelina
This data article presents a dataset of total, oligomeric alpha-synuclein and hemoglobin levels in plasma of drug-naïve PD patients and controls. This is the first attempt to assess the effect of hemolysis rate on oligomeric alpha-synuclein levels in peripheral plasma. The data are associated with the research article "Oligomeric alpha-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinson׳s disease" (Pchelina et al., 2016) [1].
February 2017: Data in Brief
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