keyword
MENU ▼
Read by QxMD icon Read
search

N370S

keyword
https://www.readbyqxmd.com/read/29676907/%C3%AE-glucocerebrosidase-modulators-promote-dimerization-of-%C3%AE-glucocerebrosidase-and-reveal-an-allosteric-binding-site
#1
Jianbin Zheng, Long Chen, Owen S Skinner, Daniel Ysselstein, Jonathan Remis, Peter Lansbury, Renato Skerlj, Michael Mrosek, Ursula Heunisch, Stephan Krapp, Joel Charrow, Michael Schwake, Neil L Kelleher, Richard B Silverman, Dimitri Krainc
β-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies...
April 20, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29530815/a-novel-p-l216i-mutation-in-the-glucocerebrosidase-gene-is-associated-with-parkinson-s-disease-in-han-chinese-patients
#2
Hong Jin, Jing Chen, Kai Li, Jin-Ru Zhang, Chen-Chen Gu, Cheng-Jie Mao, Ya-Ping Yang, Feng Wang, Chun-Feng Liu
OBJECTIVES: Pathogenic mutations in the glucocerebrosidase (GBA) gene are associated with Parkinson's disease (PD), of which L444P and N370S are the most frequently observed in patients with PD. The aim of this study was to systematically explore variations in the coding regions of GBA in Han Chinese patients with PD, as well as to expand the GBA mutation spectrum. MATERIAL AND METHODS: A total of 213 Han Chinese patients with PD and 348 controls were enrolled in the study...
March 9, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29527153/integrated-genetic-analysis-of-racial-differences-of-common-gba-variants-in-parkinson-s-disease-a-meta-analysis
#3
Yuan Zhang, Li Shu, Qiying Sun, Xun Zhou, Hongxu Pan, Jifeng Guo, Beisha Tang
Background: Numerous studies have indicated that there is a possible relationship between GBA variants and Parkinson's disease (PD), however, most of them focused on a few variants such as L444P, N370S. We performed a comprehensive pooled analysis to clarify the relationship between variations of GBA and the risk of PD in different racial groups. Methods : Standard meta-analysis was conducted, including generating inclusion and exclusion criteria, searching literature, extracting and analyzing data. Results : Fifty studies containing 20,267 PD patients and 24,807 controls were included...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29487000/glucocerebrosidase-gene-variants-are-accumulated-in-idiopathic-rem-sleep-behavior-disorder
#4
Ana Gámez-Valero, Alex Iranzo, Monica Serradell, Dolores Vilas, Joan Santamaria, Carles Gaig, Ramiro Álvarez, Aurelio Ariza, Eduardo Tolosa, Katrin Beyer
INTRODUCTION: Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically-defined LBD. METHODS: All GBA coding exons from 69 polysomnography-confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method...
February 21, 2018: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29368986/cholesterol-and-multilamellar-bodies-lyosomal-dysfunction-in-gba-parkinson-disease
#5
Patricia García-Sanz, Lorena Orgaz, José M Fuentes, Carlos Vicario, Rosario Moratalla
Lipid and cholesterol metabolism might play a role in the pathogenesis of Parkinson disease (PD). However, the association between cholesterol and PD is not clearly established. Cholesterol accumulation is closely related to the expression of multilamellar bodies (MLBs). Also, cholesterol controls autophagosome transport. Thus, impaired cholesterol and autophagosome trafficking might lead to robust autophagic vacuole accumulation. Our recent work provides the first evidence that the presence of the N370S GBA/GBA1 mutation produces an accumulation of cholesterol, which alters autophagy-lysosome function with the appearance of MLBs, rendering the cell more vulnerable and sensitive to apoptosis...
January 25, 2018: Autophagy
https://www.readbyqxmd.com/read/29311330/gba1-deficiency-negatively-affects-physiological-%C3%AE-synuclein-tetramers-and-related-multimers
#6
Sangjune Kim, Seung Pil Yun, Saebom Lee, George Essien Umanah, Veera Venkata Ratnam Bandaru, Xiling Yin, Peter Rhee, Senthilkumar S Karuppagounder, Seung-Hwan Kwon, Hojae Lee, Xiaobo Mao, Donghoon Kim, Akhilesh Pandey, Gabsang Lee, Valina L Dawson, Ted M Dawson, Han Seok Ko
Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of α-syn tetramers...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29171494/-the-clinical-features-of-parkinson-s-disease-in-patients-with-mutations-and-polymorphic-variants-of-gba-gene
#7
K A Senkevich, I V Miliukhina, M V Beletskaia, E V Gracheva, A V Kudrevatykh, M A Nikolaev, A K Emelyanov, A E Kopytova, A A Timofeeva, A F Yakimovskii, S N Pchelina
BACKGROUND: Mutations in the glucocerebrosidase gene (GBA) increase the risk of Parkinson's disease (PD) by 6-10 times in all populations and are associated with the early-onset of PD, development of cognitive impairment and presence of psychotic disorders. At the same time, polymorphic variants associated with the twofold increase in the risk of PD were also described in the GBA gene. AIM: To estimate the clinical features of PD in patients with mutations and polymorphic variants of the GBA gene...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/29090476/demographics-and-patient-characteristics-of-1209-patients-with-gaucher-disease-descriptive-analysis-from-the-gaucher-outcome-survey-gos
#8
Ari Zimran, Nadia Belmatoug, Bruno Bembi, Patrick Deegan, Deborah Elstein, Diego Fernandez-Sasso, Pilar Giraldo, Ozlem Goker-Alpan, Heather Lau, Elena Lukina, Zoya Panahloo, Ida Vanessa D Schwartz
The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy...
February 2018: American Journal of Hematology
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...
December 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28966932/frequency-of-gba-variants-in-autopsy-proven-multiple-system-atrophy
#10
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/28947706/gba-mutations-in-gaucher-type-i-venezuelan-patients-ethnic-origins-and-frequencies
#11
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/28851512/reductions-in-glucosylsphingosine-lyso-gb1-in-treatment-na%C3%A3-ve-and-previously-treated-patients-receiving-velaglucerase-alfa-for-type-1-gaucher-disease-data-from-phase-3-clinical-trials
#12
Deborah Elstein, Björn Mellgard, Quinn Dinh, Lan Lan, Yongchang Qiu, Claudia Cozma, Sabrina Eichler, Tobias Böttcher, Ari Zimran
Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (β-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD...
September 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28819579/dual-task-performance-in-gba-parkinson-s-disease
#13
Karin Srulijes, Kathrin Brockmann, Senait Ogbamicael, Markus A Hobert, Ann-Kathrin Hauser, Claudia Schulte, Jasmin Fritzen, Michael Schwenk, Thomas Gasser, Daniela Berg, Walter Maetzler
INTRODUCTION: Parkinson's disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson's disease (iPD) patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients. METHODS: Eleven GBA-PD patients (p...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/28728889/cognitive-and-motor-functioning-in-elderly-glucocerebrosidase-mutation-carriers
#14
Eileen E Moran, Cuiling Wang, Mindy Katz, Laurie Ozelius, Alison Schwartz, Jelena Pavlovic, Roberto A Ortega, Richard B Lipton, Molly E Zimmerman, Rachel Saunders-Pullman
Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson's disease and dementia with Lewy Bodies. However the penetrance of GBA mutations is low for these diseases in heterozygous carriers. The aim of this study was to examine the relationship between mutation status and cognitive and motor functioning in a sample of community-dwelling older adults. Using linear mixed effects models, we examined the effect of heterozygous mutation status on 736 community-dwelling older adults (≥70 years) without dementia or Parkinson's disease assessed over an average of 6 years, 28 of whom had a single GBA mutation (primarily N370S)...
October 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28485919/stabilization-of-glucocerebrosidase-by-active-site-occupancy
#15
Fredj Ben Bdira, Wouter W Kallemeijn, Saskia V Oussoren, Saskia Scheij, Boris Bleijlevens, Bogdan I Florea, Cindy P A A van Roomen, Roelof Ottenhoff, Marielle J F M van Kooten, Marthe T C Walvoort, Martin D Witte, Rolf G Boot, Marcellus Ubbink, Herman S Overkleeft, Johannes M F G Aerts
Glucocerebrosidase (GBA) is a lysosomal β-glucosidase that degrades glucosylceramide. Its deficiency results in Gaucher disease (GD). We examined the effects of active site occupancy of GBA on its structural stability. For this, we made use of cyclophellitol-derived activity-based probes (ABPs) that bind irreversibly to the catalytic nucleophile (E340), and for comparison, we used the potent reversible inhibitor isofagomine. We demonstrate that cyclophellitol ABPs improve the stability of GBA in vitro, as revealed by thermodynamic measurements (Tm increase by 21 °C), and introduce resistance to tryptic digestion...
July 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28468677/diagnosis-features-of-pediatric-gaucher-disease-patients-in-the-era-of-enzymatic-therapy-a-national-base-study-from-the-spanish-registry-of-gaucher-disease
#16
Marcio Andrade-Campos, Pilar Alfonso, Pilar Irun, Judith Armstrong, Carmen Calvo, Jaime Dalmau, Maria-Rosario Domingo, Jose-Luis Barbera, Horacio Cano, Maria-Angeles Fernandez-Galán, Rafael Franco, Inmaculada Gracia, Miguel Gracia-Antequera, Angela Ibañez, Francisco Lendinez, Marcos Madruga, Elena Martin-Hernández, Maria Del Mar O'Callaghan, Alberto Pérez Del Soto, Yolanda Ruiz Del Prado, Ignacio Sancho-Val, Pablo Sanjurjo, Miguel Pocovi, Pilar Giraldo
BACKGROUND: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients...
May 3, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28401966/stereodivergent-synthesis-of-right-and-left-handed-iminoxylitol-heterodimers-and-monomers-study-of-their-impact-on-%C3%AE-glucocerebrosidase-activity
#17
Fabien Stauffert, Jenny Serra-Vinardell, Marta Gómez-Grau, Helen Michelakakis, Irene Mavridou, Daniel Grinberg, Lluïsa Vilageliu, Josefina Casas, Anne Bodlenner, Antonio Delgado, Philippe Compain
A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on β-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies...
May 3, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28361101/a-molecular-analysis-of-the-gba-gene-in-caucasian-south-africans-with-parkinson-s-disease
#18
Melinda Barkhuizen, David G Anderson, Francois H van der Westhuizen, Anne F Grobler
BACKGROUND: The molecular basis of Parkinson's disease in South African population groups remains elusive. To date, substitutions in the GBA gene are the most common large-effect genetic risk factor for Parkinson's disease. The primary objective of this study was to determine the prevalence of GBA substitutions in South Africans with idiopathic Parkinson's disease. METHODS: Participants were recruited from tertiary hospitals in the Gauteng Province in South Africa...
March 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28185830/children-with-type-1-gaucher-disease-changing-profiles-in-the-21st-century
#19
Deborah Elstein, Gheona Altarescu, Aya Abrahamov, Ari Zimran
Gaucher disease (GD) has phenotypic variability. Increased GD awareness especially among at-risk Ashkenazi Jews (AJ) and availability of non-invasive diagnosis induced trend to prenatal screening. We retrospectively assessed pediatric (<16years) Israeli AJ GD patients to ascertain demographics and phenotype at presentation and over-time because many were identified by large-scale screening. 55/67 patients born since 01/01/2000 are AJ with non-neuronopathic GD: 28 (50.9%) are N370S/N370S; 24 (43.6%) are N370S/other; 3 (3...
February 2018: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28034821/prevalence-of-autoantibodies-in-the-course-of-gaucher-disease-type-1-a-multicenter-study-comparing-gaucher-disease-patients-to-healthy-subjects
#20
Christine Serratrice, Nesma Bensalah, Guillaume Penaranda, Nathalie Bardin, Nadia Belmatoug, Agathe Masseau, Christian Rose, Olivier Lidove, Fabrice Camou, François Maillot, Vanessa Leguy, Nadine Magy-Bertrand, Isabelle Marie, Patrick Cherin, Monia Bengherbia, Sebastian Carballo, José Boucraut, Jacques Serratrice, Marc Berger, Denis Verrot
OBJECTIVES: Type 1 Gaucher disease may be related to the presence of autoantibodies. Their clinical significance is questioned. Primary endpoint was to compare the prevalence of autoantibodies in type 1 Gaucher disease patients with healthy subjects, seeking correlations with autoimmune characteristics. Secondary endpoints were to determine whether patients with autoantibodies reported autoimmunity-related symptoms and if genotype, splenectomy or treatment influenced autoantibodies presence...
January 2018: Joint, Bone, Spine: Revue du Rhumatisme
keyword
keyword
83513
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"