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Glucocerebrosidase

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https://www.readbyqxmd.com/read/28944282/progranulin-acts-as-a-shared-chaperone-and-regulates-multiple-lysosomal-enzymes
#1
Jinlong Jian, Aubryanna Hettinghouse, Chuan-Ju Liu
Multifunctional factor progranulin (PGRN) plays an important role in lysosomes, and its mutations and insufficiency are associated with lysosomal storage diseases, including neuronal ceroid lipofuscinosis and Gaucher disease (GD). The first breakthrough in understanding the molecular mechanisms of PGRN as regulator of lysosomal storage diseases came unexpectedly while investigating the role of PGRN in inflammation. Challenged PGRN null mice displayed typical features of GD. In addition, GRN gene variants were identified in GD patients and the serum levels of PGRN were significantly lower in GD patients...
September 2017: Genes & Diseases
https://www.readbyqxmd.com/read/28933588/death-by-over-eating-the-gaucher-disease-associated-gene-gba1-identified-in-a-screen-for-mediators-of-autophagic-cell-death-is-necessary-for-developmental-cell-death-in-drosophila-midgut
#2
Santosh K Dasari, Eyal Schejter, Shani Bialik, Aya Shkedy, Vered Levin-Salomon, Smadar Levin-Zaidman, Adi Kimchi
Autophagy is critical for homeostasis and cell survival during stress, but can also lead to cell death, a little understood process that has been shown to contribute to developmental cell death in lower model organisms, and to human cancer cell death. We recently reported (1) on our thorough molecular and morphologic characterization of an autophagic cell death system involving resveratrol treatment of lung carcinoma cells. To gain mechanistic insight into this death program, we performed a signalome-wide RNAi screen for genes whose functions are necessary for resveratrol-induced death...
September 21, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28933411/mitochondrial-dysfunction-in-lysosomal-storage-disorders
#3
REVIEW
Mario de la Mata, David Cotán, Marina Villanueva-Paz, Isabel de Lavera, Mónica Álvarez-Córdoba, Raquel Luzón-Hidalgo, Juan M Suárez-Rivero, Gustavo Tiscornia, Manuel Oropesa-Ávila
Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS), where neuronal dysfunction or loss results in progressive neurodegeneration and premature death...
October 11, 2016: Diseases (Basel)
https://www.readbyqxmd.com/read/28933363/the-spectrum-of-neurological-manifestations-associated-with-gaucher-disease
#4
REVIEW
Tamanna Roshan Lal, Ellen Sidransky
Gaucher disease, the most common lysosomal storage disorder, is due to a deficiency in the enzyme glucocerebrosidase. This leads to the accumulation of its normal substrate, glucocerebroside, in tissue macrophages, affecting the hematological, visceral, bone and neurologic systems. Gaucher disease is classified into three broad phenotypes based upon the presence or absence of neurological involvement: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Phenotypically, there is a wide spectrum of visceral and neurological manifestations...
March 2, 2017: Diseases (Basel)
https://www.readbyqxmd.com/read/28925361/generation-of-a-homozygous-gba-deletion-human-embryonic-stem-cell-line
#5
Anna Lisa Gündner, Claas Aiko Meyer, Stefan Aigner, Klaus Christensen, Christoph Patsch, Ravi Jagasia, Karlheinz Baumann, Mark Burcin
We describe the generation of a biallelic GBA deletion human embryonic stem cell line using zinc finger nuclease-mediated gene targeting. The homozygous targeting of exon 4 of the GBA locus leads to a complete loss of glucocerebrosidase (GCase) protein expression.
August 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28905961/correction-stereodivergent-synthesis-of-right-and-left-handed-iminoxylitol-heterodimers-and-monomers-study-of-their-impact-on-%C3%AE-glucocerebrosidase-activity
#6
Fabien Stauffert, Jenny Serra-Vinardell, Marta Gómez-Grau, Helen Michelakakis, Irene Mavridou, Daniel Grinberg, Lluïsa Vilageliu, Josefina Casas, Anne Bodlenner, Antonio Delgado, Philippe Compain
Correction for 'Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity' by Fabien Stauffert et al., Org. Biomol. Chem., 2017, 15, 3681-3705.
September 14, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28890071/serum-lipid-alterations-in-gba-associated-parkinson-s-disease
#7
Leonor Correia Guedes, Robin Barry Chan, Marcos António Gomes, Vasco A Conceição, Raquel Bouça Machado, Tiago Soares, Yimeng Xu, Paulo Gaspar, Joao André Carriço, Roy N Alcalay, Joaquim J Ferreira, Tiago Fleming Outeiro, Gabriel Miltenberger-Miltenyi
INTRODUCTION: Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations. METHODS: We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2...
September 1, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28882997/dopamine-oxidation-mediates-mitochondrial-and-lysosomal-dysfunction-in-parkinson-s-disease
#8
Lena F Burbulla, Pingping Song, Joseph R Mazzulli, Enrico Zampese, Yvette C Wong, Sohee Jeon, David P Santos, Judith Blanz, Carolin D Obermaier, Chelsee Strojny, Jeffrey N Savas, Evangelos Kiskinis, Xiaoxi Zhuang, Rejko Krüger, D James Surmeier, Dimitri Krainc
Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation...
September 22, 2017: Science
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
#9
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/28843015/cerebrospinal-fluid-%C3%AE-glucocerebrosidase-activity-is-reduced-in-parkinson-s-disease-patients
#10
Lucilla Parnetti, Silvia Paciotti, Paolo Eusebi, Andrea Dardis, Stefania Zampieri, Davide Chiasserini, Anna Tasegian, Nicola Tambasco, Bruno Bembi, Paolo Calabresi, Tommaso Beccari
BACKGROUND: Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower β-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced β-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF...
August 26, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28835999/glucocerebrosidase-expression-patterns-in-the-non-human-primate-brain
#11
Iria G Dopeso-Reyes, Diego Sucunza, Alberto J Rico, Diego Pignataro, David Marín-Ramos, Elvira Roda, Ana I Rodríguez-Pérez, José L Labandeira-García, José L Lanciego
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher's disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson's disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date...
August 23, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28834018/gba-mutations-in-parkinson-disease-earlier-death-but-similar-neuropathological-features
#12
C H Adler, T G Beach, H A Shill, J N Caviness, E Driver-Dunckley, M N Sabbagh, A Patel, L I Sue, G Serrano, S A Jacobson, K Davis, C M Belden, B N Dugger, S A Paciga, A R Winslow, W D Hirst, J G Hentz
BACKGROUND AND PURPOSE: Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. METHODS: Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation...
August 17, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
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/28802918/genes-and-nonmotor-symptoms-in-parkinson-s-disease
#14
Ee-Wei Lim, Eng-King Tan
Published data on genetic risk factors of nonmotor symptoms (NMS) are relatively lacking since the first mutation responsible for Parkinson's disease (PD) being reported in 1996. This chapter provides a concise summary of genetic links to common individual NMS such as cognitive impairment, depression, psychosis, olfactory dysfunction, pain, and sleep disorders. Although some genetic variants such as apolipoprotein E and glucocerebrosidase demonstrate consistent links with certain NMS, it is difficult to draw definitive conclusions...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28763689/investigation-of-novel-pharmacological-chaperones-for-gaucher-disease
#15
Buge Yilmazer, Z Begum Yagci, Emre Bakar, Burcu Ozden, Kutlu Ulgen, Elif Ozkirimli
Beta-Glucocerebrosidase (GBA) is a lysosomal protein that is responsible for the hydrolysis of glycosylceramide into glucose and ceramide. Mutations in GBA lead to the accumulation of glycosylceramide in the lysosome causing an enlargement of the spleen and the liver and skeletal deformations. This disease is called Gaucher Disease. Enzyme replacement therapies and substrate reduction methods that are used to treat Gaucher Disease fail when the disease is neuropathic because they fail to pass the blood brain barrier...
July 20, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28749998/lc-ms-ms-multiplex-analysis-of-lysosphingolipids-in-plasma-and-amniotic-fluid-a-novel-tool-for-the-screening-of-sphingolipidoses-and-niemann-pick-type-c-disease
#16
Magali Pettazzoni, Roseline Froissart, Cécile Pagan, Marie T Vanier, Séverine Ruet, Philippe Latour, Nathalie Guffon, Alain Fouilhoux, Dominique P Germain, Thierry Levade, Christine Vianey-Saban, Monique Piraud, David Cheillan
BACKGROUND: The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma. METHODOLOGY: We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i...
2017: PloS One
https://www.readbyqxmd.com/read/28744000/permeability-barrier-and-microstructure-of-skin-lipid-membrane-models-of-impaired-glucosylceramide-processing
#17
Michaela Sochorová, Klára Staňková, Petra Pullmannová, Andrej Kováčik, Jarmila Zbytovská, Kateřina Vávrová
Ceramide (Cer) release from glucosylceramides (GlcCer) is critical for the formation of the skin permeability barrier. Changes in β-glucocerebrosidase (GlcCer'ase) activity lead to diminished Cer, GlcCer accumulation and structural defects in SC lipid lamellae; however, the molecular basis for this impairment is not clear. We investigated impaired GlcCer-to-Cer processing in human Cer membranes to determine the physicochemical properties responsible for the barrier defects. Minor impairment (5-25%) of the Cer generation from GlcCer decreased the permeability of the model membrane to four markers and altered the membrane microstructure (studied by X-ray powder diffraction and infrared spectroscopy), in agreement with the effects of topical GlcCer in human skin...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28741230/new-therapeutic-strategies-for-lewy-body-dementias
#18
REVIEW
Latha Velayudhan, Dominic Ffytche, Clive Ballard, Dag Aarsland
This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias...
September 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28736246/in-vitro-osteoclastogenesis-from-gaucher-patients-cells-correlates-with-bone-mineral-density-but-not-with-chitotriosidase
#19
C Bondar, J Mucci, A Crivaro, M Ormazabal, R Ceci, B Oliveri, D González, P Rozenfeld
Gaucher disease (GD) is caused by mutations on the gene encoding for the lysosomal enzyme glucocerebrosidase. Type I GD (GD1) patients present anemia, hepatosplenomegaly and bone alterations. In spite of treatment, bone alterations in GD patients persist, including poor bone mineral density (BMD). Mechanisms leading to bone damage are not completely understood, but previous reports suggest that osteoclasts are involved. Chitotriosidase (CHIT) is the most reliable biomarker used in the follow up of patients, although its correlation with bone status is unknown...
July 20, 2017: Bone
https://www.readbyqxmd.com/read/28728889/cognitive-and-motor-functioning-in-elderly-glucocerebrosidase-mutation-carriers
#20
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)...
June 24, 2017: Neurobiology of Aging
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