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https://www.readbyqxmd.com/read/29140481/excessive-burden-of-lysosomal-storage-disorder-gene-variants-in-parkinson-s-disease
#1
Laurie A Robak, Iris E Jansen, Jeroen van Rooij, André G Uitterlinden, Robert Kraaij, Joseph Jankovic, Peter Heutink, Joshua M Shulman
Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk...
November 13, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29133411/specific-inhibition-of-gpcr-independent-g-protein-signaling-by-a-rationally-engineered-protein
#2
Anthony Leyme, Arthur Marivin, Marcin Maziarz, Vincent DiGiacomo, Maria P Papakonstantinou, Prachi P Patel, Juan B Blanco-Canosa, Isha A Walawalkar, Gonzalo Rodriguez-Davila, Isabel Dominguez, Mikel Garcia-Marcos
Activation of heterotrimeric G proteins by cytoplasmic nonreceptor proteins is an alternative to the classical mechanism via G protein-coupled receptors (GPCRs). A subset of nonreceptor G protein activators is characterized by a conserved sequence named the Gα-binding and activating (GBA) motif, which confers guanine nucleotide exchange factor (GEF) activity in vitro and promotes G protein-dependent signaling in cells. GBA proteins have important roles in physiology and disease but remain greatly understudied...
November 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29129675/alpha-synuclein-dimerization-in-erythrocytes-of-patients-with-genetic-and-non-genetic-forms-of-parkinson-s-disease
#3
Nikolaos Papagiannakis, Christos Koros, Maria Stamelou, Athina-Maria Simitsi, Matina Maniati, Roubina Antonelou, Dimitra Papadimitriou, Georgia Dermentzaki, Marina Moraitou, Helen Michelakakis, Leonidas Stefanis
BACKGROUND: Variations of α-synuclein levels or species have been reported in Parkinson's Disease (PD). There has been little systematic examination of erythrocytes, a rich source of α-synuclein. METHODS: Erythrocyte membranes were obtained from PD patients (mutation carriers in the α-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric α-synuclein were assessed using Western immunoblotting...
November 9, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29124790/neuropathology-of-genetic-synucleinopathies-with-parkinsonism-review-of-the-literature
#4
REVIEW
Susanne A Schneider, Roy N Alcalay
Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3)...
November 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29100779/tandem-mass-spectrometry-assay-of-%C3%AE-glucocerebrosidase-activity-in-dried-blood-spots-eliminates-false-positives-detected-in-fluorescence-assay
#5
Pavlina Wolf, Roy N Alcalay, Christopher Liong, Emmaline Cullen, Michael W Pauciulo, William C Nichols, Ziv Gan-Or, Wendy K Chung, Tina Faulkner, Christopher Bentis, Robert J Pomponio, Xiwen Ma, X Kate Zhang, Joan M Keutzer, Petra Oliva
Deficiency of β-Glucocerebrosidase (GBA) activity causes Gaucher Disease (GD). GD can be diagnosed by measuring GBA activity (Beutler and Kuhl, 1990). In this study, we assayed dried blood spots from a cohort (n=528) enriched for GBA mutation carriers (n=78) and GD patients (n=18) using both the tandem mass spectrometry (MS/MS) and fluorescence assays and their respective synthetic substrates. The MS/MS assay differentiated normal controls, which included GBA mutation carriers, from GD patients with no overlap...
October 23, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29094781/cognitive-impairment-in-glucocerebrosidase-gba-associated-pd-not-primarily-associated-with-cerebrospinal-fluid-abeta-and-tau-profiles
#6
Stefanie Lerche, Claudia Schulte, Karin Srulijes, Andrea Pilotto, Tim W Rattay, Ann-Kathrin Hauser, Elke Stransky, Christian Deuschle, Ilona Csoti, Ingolf Lachmann, Henrik Zetterberg, Inga Liepelt-Scarfone, Thomas Gasser, Walter Maetzler, Daniela Berg, Kathrin Brockmann
BACKGROUND: A proportion of idiopathic Parkinson's disease patients (PDidiopathic ) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA ) present with even more cognitive decline than seen in PDidiopathic . OBJECTIVE: The objective of this study was to evaluate whether CSF profiles of Aβ and tau are associated with the prominent cognitive impairment in PDGBA . METHODS: CSF levels of Aβ1-42 , t-Tau, p-Tau, and total alpha-synuclein were assessed in 479 participants (50 PDGBA , 308 PDidiopathic , 121 healthy controls)...
November 2, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29092678/spectrum-of-female-commercial-sex-work-in-bangui-central-african-republic
#7
Jean De Dieu Longo, Marcel Mbéko Simaléko, Richard Ngbale, Gérard Grésenguet, Gilles Brücker, Laurent Bélec
Classification of professional and non-professional female sex workers (FSWs) into different categories, never previously reported in the Central African Republic (CAR), may be useful to assess the dynamics of the human immunodeficiency virus (HIV) epidemic, design operational intervention programmes to combat HIV and other sexually transmitted infections (STIs) and to adapt these programmes to the broad spectrum of sexual transactions in the CAR. Our study proposes a socio-behavioural classification of FSWs living in the CAR and engaged in transactional and commercial sex...
December 2017: SAHARA J: Journal of Social Aspects of HIV/AIDS Research Alliance
https://www.readbyqxmd.com/read/29035513/when-heterotrimeric-g-proteins-are-not-activated-by-g-protein-coupled-receptors-structural-insights-and-evolutionary-conservation
#8
Vincent DiGiacomo, Arthur Marivin, Mikel Garcia-Marcos
Heterotrimeric G proteins are signal-transducing switches conserved across eukaryotes. In humans, they work as critical mediators of intercellular communication in the context of virtually any physiological process. While G protein regulation by G protein-coupled receptors (GPCRs) is well-established and has received much attention, it has become recently evident that heterotrimeric G proteins can also be activated by cytoplasmic proteins. However, this alternative mechanism of G protein regulation remains far less studied than GPCR-mediated signaling...
October 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/29029963/genetic-risk-factors-in-finnish-patients-with-parkinson-s-disease
#9
Susanna Ylönen, Ari Siitonen, Michael A Nalls, Pauli Ylikotila, Jaana Autere, Johanna Eerola-Rautio, Raphael Gibbs, Mikko Hiltunen, Pentti J Tienari, Hilkka Soininen, Andrew B Singleton, Kari Majamaa
INTRODUCTION: Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS: The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls...
September 29, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29025868/in-situ-visualization-of-glucocerebrosidase-in-human-skin-tissue-zymography-vs-activity-based-probe-labeling
#10
Jeroen van Smeden, Irini M Dijkhoff, Richard W J Helder, Hanin Al-Khakany, Daphne E C Boer, Anne Schreuder, Wouter W Kallemeijn, Samira Absalah, Herman S Overkleeft, Johannes M F G Aerts, Joke A Bouwstra
Epidermal glucocerebrosidase (GBA1), an acid β-glucosidase normally located in lysosomes, converts (glucosyl)ceramides into ceramides, which is crucial to generate an optimal barrier function of the outermost skin layer, the stratum corneum. Here we report on two developed in-situ methods to localize active GBA in human epidermis: i) an optimized zymography method that is less labour intensive and visualizes enzymatic activity with higher resolution than currently reported methods using either substrate 4-methylumbelliferyl-β-D-glucopyranoside or resorufin-β-D-glucopyranoside...
October 12, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28991672/clinical-profiles-associated-with-lrrk2-and-gba-mutations-in-brazilians-with-parkinson-s-disease
#11
Camilla P da Silva, Gabriella de M Abreu, Pedro H Cabello Acero, Mário Campos, João S Pereira, Sarah R de A Ramos, Caroline M Nascimento, Danielle D Voigt, Ana Lucia Rosso, Marco A Araujo Leite, Luiz Felipe R Vasconcellos, Denise H Nicaretta, Marcus V Della Coletta, Delson José da Silva, Andressa P Gonçalves, Jussara M Dos Santos, Veluma Calassara, Débora Cristina T Valença, Cyro J de M Martins, Cíntia B Santos-Rebouças, Márcia M G Pimentel
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by remarkable phenotypic variability. Accumulated evidence points that the manifestation of PD clinical signs might be differentially modified by genetic factors, as mutations in LRRK2 and GBA genes. In this sense, the clarification of the genotype-phenotype correlations in PD has important implications in predicting prognosis and can contribute to the development of specific therapeutic approaches. METHODS: Here, we conducted the first comparative analysis of motor and non-motor features in 17 LRRK2 and 22 GBA mutation carriers and 93 non-carriers unrelated PD patients from Brazil, a highly admixed population...
October 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28983119/the-gbap1-pseudogene-acts-as-a-cerna-for-the-glucocerebrosidase-gene-gba-by-sponging-mir-22-3p
#12
Letizia Straniero, Valeria Rimoldi, Maura Samarani, Stefano Goldwurm, Alessio Di Fonzo, Rejko Krüger, Michela Deleidi, Massimo Aureli, Giulia Soldà, Stefano Duga, Rosanna Asselta
Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson's disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating GBA expression. We explored the existence of a regulatory network involving GBA, its expressed pseudogene GBAP1, and microRNAs. The high level of sequence identity between GBA and GBAP1 makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge...
October 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28982173/induced-gamma-band-activity-from-eeg-as-a-possible-index-of-training-related-brain-plasticity-in-motor-tasks
#13
Carlos Amo, Luis De Santiago, Daniel Zarza Luciáñez, José Miguel León Alonso-Cortés, Miguel Alonso-Alonso, Rafael Barea, Luciano Boquete
The aim of this study was proposing gamma band activity (GBA) as an index of training-related brain plasticity in the motor cortex. Sixteen controls underwent an experimental session where electroencephalography (EEG) activity was recorded at baseline (resting) and during a motor task (hand movements). GBA was obtained from the EEG data at baseline and during the task. Index of plasticity (IP) was defined as the relationship between GBA at the end of the motor task (GBAM_FIN), divided by GBA at the beginning of the task (GBAM_INI) for movements of both hands...
2017: PloS One
https://www.readbyqxmd.com/read/28966932/frequency-of-gba-variants-in-autopsy-proven-multiple-system-atrophy
#14
Miriam Sklerov, Un Jung Kang, Christopher Liong, Lorraine Clark, Karen Marder, Michael Pauciulo, William C Nichols, Wendy K Chung, Lawrence S Honig, Etty Cortes, Jean Paul Vonsattel, Roy N Alcalay
BACKGROUND: Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. OBJECTIVES: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City...
July 2017: Movement Disorders Clinical Practice
https://www.readbyqxmd.com/read/28964333/rapid-kinetic-bret-measurements-to-monitor-g-protein-activation-by-gpcr-and-non-gpcr-proteins
#15
Marcin Maziarz, Mikel Garcia-Marcos
Heterotrimeric G proteins are central hubs of signal transduction whose activity is controlled by G protein-coupled receptors (GPCRs) as well as by a complex network of regulatory proteins. Recently, bioluminescence resonance energy transfer (BRET)-based assays have been used to monitor real-time activation of heterotrimeric G proteins in cells. Here we describe the use of a previously established BRET assay to monitor G protein activation upon GPCR stimulation and its adaptation to measure G protein activation by non-GPCR proteins, such as by cytoplasmic guanine nucleotide exchange factors (GEFs) like GIV/Girdin...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28964332/fluorescence-polarization-assays-to-measure-interactions-between-g%C3%AE-subunits-of-heterotrimeric-g-proteins-and-regulatory-motifs
#16
Marcin Maziarz, Mikel Garcia-Marcos
Fluorescence polarization (FP) is a simple and sensitive method allowing for the quantification of interactions between proteins and fluorescently tagged small molecules like peptides. Heterotrimeric G proteins are critical signal transducing molecules and their activity is controlled by a complex network of regulatory proteins. Some of these regulators have defined short motifs (<40 amino acids) that are sufficient to bind G proteins and subsequently modulate their activity. For these cases, FP represents a robust and quantitative method to characterize the G protein regulator interaction...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28963610/patients-opinions-on-genetic-counseling-on-the-increased-risk-of-parkinson-disease-among-gaucher-disease-carriers
#17
Maureen Mulhern, Louise Bier, Roy N Alcalay, Manisha Balwani
Gaucher disease (GD) is an autosomal recessive disease caused by GBA mutations that is especially common in the Ashkenazi Jewish (AJ) population. The link between GBA mutations and Parkinson disease (PD), a later-onset neurodegenerative condition, is well established, and studies have shown that GBA carriers have an increased lifetime risk of developing PD. Carrier screening for GD is frequently offered to couples during or prior to pregnancy, especially to those of AJ descent. However, no studies have been performed to assess if prospective parents would want to learn about their risk of developing PD incidentally through carrier screening...
September 30, 2017: Journal of Genetic Counseling
https://www.readbyqxmd.com/read/28947706/gba-mutations-in-gaucher-type-i-venezuelan-patients-ethnic-origins-and-frequencies
#18
Gilberto Gómez, Sergio Arias, Leonor Cárdenas, Dalal Zoghbi, Irene Paradisi
Gaucher disease (GD), the most frequent lysosomal storage disease, is caused by heterogeneous mutations in the locus coding for glucocerebrosidase (GBA). It is an autosomal recessive disorder with different phenotypes of which the most frequent is the nonneuronopathic or type 1, prevalent worldwide. To date, more than 430 mutations have been described, but their frequency distribution varies in different populations with four, N370S, L444P, IVS2 + 1G > A and 84insG, being the most frequent ones. In Venezuela, 20 unrelated index cases with GD type I were assessed for GBA mutation detection and for their in-phase haplotype identification, to gather genetic epidemiological data on the disease in the country and of its eventual ethnic origin...
September 2017: Journal of Genetics
https://www.readbyqxmd.com/read/28937220/a-fluorescence-polarization-activity-based-protein-profiling-assay-in-the-discovery-of-potent-selective-inhibitors-for-human-nonlysosomal-glucosylceramidase
#19
Daniël Lahav, Bing Liu, Richard J B H N van den Berg, Adrianus M C H van den Nieuwendijk, Tom Wennekes, Amar T Ghisaidoobe, Imogen Breen, Maria J Ferraz, Chi-Lin Kuo, Liang Wu, Paul P Geurink, Huib Ovaa, Gijsbert A van der Marel, Mario van der Stelt, Rolf G Boot, Gideon J Davies, Johannes M F G Aerts, Herman S Overkleeft
Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3...
October 11, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28934417/production-of-3-geranyl-4-hydroxybenzoate-acid-in-yeast-an-important-intermediate-of-shikonin-biosynthesis-pathway
#20
Sheng Wang, Ruishan Wang, Tan Liu, Zhilai Zhan, Liping Kang, Yanan Wang, Chaogeng Lv, Daniele Werck-Reichhart, Lanping Guo, Luqi Huang
Shikonin and its derivatives are the main active components in the medicinal plant Arnebia euchroma and possess extensive pharmaceutical properties. In this study, we developed an optimized yeast system to obtain high-level production of 3-geranyl-4-hydroxybenzoate acid (GBA), an important intermediate involved in shikonin biosynthesis pathway. For host selection, recombinant expression of p-hydroxybenzoate:geranyltransferase (PGT) derived from A. euchroma was performed in Saccharomyces cerevisiae WAT11U strain and high yield monoterpene strain...
November 1, 2017: FEMS Yeast Research
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