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Glucocerebrosidase

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https://www.readbyqxmd.com/read/29792872/association-of-glucocerebrosidase-polymorphisms-and-mutations-with-dementia-in-incident-parkinson-s-disease
#1
Kristin Aaser Lunde, Janete Chung, Ingvild Dalen, Kenn Freddy Pedersen, Jan Linder, Magdalena E Domellöf, Eva Elgh, Angus D Macleod, Charalampos Tzoulis, Jan Petter Larsen, Ole-Bjørn Tysnes, Lars Forsgren, Carl E Counsell, Guido Alves, Jodi Maple-Grødem
INTRODUCTION: Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease. METHODS: Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis...
May 21, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/29784561/parkinson-s-disease-phenotype-is-influenced-by-the-severity-of-the-mutations-in-the-gba-gene
#2
Avner Thaler, Noa Bregman, Tanya Gurevich, Tamara Shiner, Yonatan Dror, Ofir Zmira, Ziv Gan-Or, Anat Bar-Shira, Mali Gana-Weisz, Avi Orr-Urtreger, Nir Giladi, Anat Mirelman
OBJECTIVE: Mutations in the glucocerebrosidase (GBA) gene are divided into mild and severe (mGBA, sGBA) based on their contribution to the phenotype of Gaucher disease (GD) among homozygotes. We conducted a longitudinal analysis of Parkinson's disease (PD) patients carrying mutations in the GBA gene to better characterize genotype-phenotype correlations. METHODS: Patients underwent a comprehensive assessment of medical, neurological, cognitive and non-motor functions...
May 17, 2018: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29750678/ce-understanding-the-nurse-s-role-in-managing-gaucher-disease
#3
Erika R Vucko
How advances in screening, diagnosis, and treatment affect patient care. ABSTRACT: Lysosomal storage disorders (LSDs) are a group of inherited metabolic conditions, the overall incidence of which is estimated to range from one in 5,000 to one in 7,000 live births. Gaucher disease, the most common LSD, is of autosomal recessive inheritance. It results from a deficiency of acid β-glucocerebrosidase and can affect the spleen, liver, bone, bone marrow, and central nervous system. Gaucher disease is clinically classified into one of three phenotypes, depending on the absence or presence of neurodegenerative disease and the rate of disease progression...
May 11, 2018: American Journal of Nursing
https://www.readbyqxmd.com/read/29746165/a-lysosome-plasma-membrane-sphingolipid-axis-linking-lysosomal-storage-to-cell-growth-arrest
#4
Maura Samarani, Nicoletta Loberto, Giulia Soldà, Letizia Straniero, Rosanna Asselta, Stefano Duga, Giulia Lunghi, Fabio A Zucca, Laura Mauri, Maria Grazia Ciampa, Domitilla Schiumarini, Rosaria Bassi, Paola Giussani, Elena Chiricozzi, Alessandro Prinetti, Massimo Aureli, Sandro Sonnino
Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose-loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids ( i...
May 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29735704/lrrk2-phosphorylation-of-auxilin-mediates-synaptic-defects-in-dopaminergic-neurons-from-patients-with-parkinson-s-disease
#5
Maria Nguyen, Dimitri Krainc
Recently identified Parkinson's disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29735433/glycosphingolipid-levels-and-glucocerebrosidase-activity-are-altered-in-normal-aging-of-the-mouse-brain
#6
Penelope J Hallett, Mylene Huebecker, Oeystein R Brekk, Elizabeth B Moloney, Emily M Rocha, David A Priestman, Frances M Platt, Ole Isacson
Aging is the predominant risk factor for both genetic and sporadic Parkinson's disease (PD). The majority of PD cases are nonfamilial, and the connection between aging and PD-associated genes is not well understood. Haploinsufficiency of the GBA gene, leading to a reduction in glucocerebrosidase (GCase) activity, is one of the most common genetic risk factors for PD. Furthermore, GCase activity is also reduced in brain regions of sporadic PD patients, with a corresponding accumulation of its glycosphingolipid (GSL) substrates...
March 29, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29704272/targeted-therapies-for-parkinson-s-disease-from-genetics-to-the-clinic
#7
REVIEW
S Pablo Sardi, Jesse M Cedarbaum, Patrik Brundin
The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease-modifying treatments based on knowledge of PD genetics and pathology...
April 27, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29703245/d409h-gba1-mutation-accelerates-the-progression-of-pathology-in-a53t-%C3%AE-synuclein-transgenic-mouse-model
#8
Donghoon Kim, Heehong Hwang, Seulah Choi, Sang Ho Kwon, Suhyun Lee, Jae Hong Park, SangMin Kim, Han Seok Ko
Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson's disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice...
April 27, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29700232/3-4-dihydroxyphenylacetaldehyde-dopal-induced-protein-modifications-and-their-mitigation-by-n-acetylcysteine
#9
Yunden Jinsmaa, Yehonatan Sharabi, Patti Sullivan, Risa Isonaka, David S Goldstein
The catecholaldehyde hypothesis posits that 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediary metabolite of dopamine (DA), is an autotoxin that challenges neuronal homeostasis in catecholaminergic neurons. DOPAL toxicity may involve protein modifications, such as oligomerization of alpha-synuclein (AS). Potential interactions between DOPAL and other proteins related to catecholaminergic neurodegeneration, however, have not been systemically explored. This study examined DOPAL-induced protein-quinone adduct formation ("quinonization") and protein oligomerization, ubiquitination, and aggregation in cultured MO3...
April 26, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29699937/molecular-regulations-and-therapeutic-targets-of-gaucher-disease
#10
REVIEW
Yuehong Chen, Neetu Sud, Aubryanna Hettinghouse, Chuan-Ju Liu
Gaucher disease (GD) is the most common lysosomal storage disease caused by deficiency of beta-glucocerebrosidase (GCase) resulting in lysosomal accumulation of its glycolipid substrate glucosylceramide. The activity of GCase depends on many factors such as proper folding and lysosomal localization, which are influenced by mutations in GCase encoding gene, and regulated by various GCase-binding partners including Saposin C, progranulin and heat shock proteins. In addition, proinflammatory molecules also contribute to pathogenicity of GD...
April 11, 2018: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/29696051/are-there-neurological-symptoms-in-type-1-of-gaucher-disease
#11
Mohammadreza Alaei, Narjes Jafari, Farzaneh Rohani, Farzad Ahmadabadi, Rezvan Azadi
Objective: Gaucher disease (GD) is a rare inborn error of metabolism, classified as a lipid storage disorders. This disease is caused by a deficiency in glucocerebrosidase enzyme. It has been classified according to the presence or absence of neurological symptoms into the following types: type 1 non-neuropathic, type 2 acute infantile neuropathic and type 3 or chronic neuropathic. We evaluated neurological symptoms in patients with GD1 and GD3 and compared both of these groups. Materials & Methods: Eleven patients were identified according to their clinical presentation and the presence of disease confirmed by genetic testing, from 2006-2016, at the Mofid Children Hospital Clinic, Tehran, Iran...
2018: Iranian Journal of Child Neurology
https://www.readbyqxmd.com/read/29695488/characterization-of-lamp1-labeled-nondegradative-lysosomal-and-endocytic-compartments-in-neurons
#12
Xiu-Tang Cheng, Yu-Xiang Xie, Bing Zhou, Ning Huang, Tamar Farfel-Becker, Zu-Hang Sheng
Despite widespread distribution of LAMP1 and the heterogeneous nature of LAMP1-labeled compartments, LAMP1 is routinely used as a lysosomal marker, and LAMP1-positive organelles are often referred to as lysosomes. In this study, we use immunoelectron microscopy and confocal imaging to provide quantitative analysis of LAMP1 distribution in various autophagic and endolysosomal organelles in neurons. Our study demonstrates that a significant portion of LAMP1-labeled organelles do not contain detectable lysosomal hydrolases including cathepsins D and B and glucocerebrosidase...
April 25, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29676907/%C3%AE-glucocerebrosidase-modulators-promote-dimerization-of-%C3%AE-glucocerebrosidase-and-reveal-an-allosteric-binding-site
#13
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/29673163/probing-the-inhibitor-versus-chaperone-properties-of-sp%C3%A2-iminosugars-towards-human-%C3%AE-glucocerebrosidase-a-picomolar-chaperone-for-gaucher-disease
#14
Teresa Mena-Barragán, M Isabel García-Moreno, Alen Sevšek, Tetsuya Okazaki, Eiji Nanba, Katsumi Higaki, Nathaniel I Martin, Roland J Pieters, José M García Fernández, Carmen Ortiz Mellet
A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d- gluco or l- ido ), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′ -octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase)...
April 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29644751/disease-modification-in-parkinson-s-disease-current-approaches-challenges-and-future-considerations
#15
REVIEW
Anthony E Lang, Alberto J Espay
The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis...
April 11, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29625627/a-pilot-screening-of-high-risk-gaucher-disease-children-using-dried-blood-spot-methods-in-shandong-province-of-china
#16
Ke Lei, Yanxia Zhao, Lirong Sun, Hui Liang, Ronghua Luo, Xiaojing Sun, Yanling Tao, Lijun Chen, Lingling Zhang, Aimin Li, Fu Li, Hongfang Ding
BACKGROUND: The study aim was to verify the feasibility of a diagnostic algorithm with the evaluation of beta glucocerebrosidase (GBA) activity on dried blood spots (DBS) in screening high-risk Gaucher disease (GD) children in China, and to investigate the GD prevalence in this selected population. METHODS: Children were recruited from 20 departments of pediatrics or children's hospitals in Shandong Province, China, due to splenomegaly and/or thrombocytopenia associated with one or more of the following creteria: anemia, history of bone pain, monoclonal gammopathy of unknown significance (MGUS), polyclonal gammopathy and splenectomy...
April 6, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29610006/-type-3-gaucher-disease-also-an-adult-disease
#17
A Leurs, A Chepy, C Detonellaere, L Pascal, P Gallois, T-A-C Tran, C Caillaud, P-Y Hatron, C Rose
INTRODUCTION: Gaucher disease is a genetic lysosomal storage disorder due to a glucocerebrosidase deficiency. Type 3, including neurological impairment, may have a specific phenotype in the context of the D409H mutation. OBSERVATION: We report the case of a 22-year-old woman who presented with Gaucher disease. Enzyme replacement therapy by imiglucerase was followed by rapid clinical and biological improvement. However, communication difficulties, which were initially attributed to the language barrier, revealed neurological impairment...
March 30, 2018: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/29602947/high-risk-screening-for-gaucher-disease-in-patients-with-neurological-symptoms
#18
Ken Momosaki, Jun Kido, Shirou Matsumoto, Shinichiro Yoshida, Atsuko Takei, Takuya Miyabayashi, Keishin Sugawara, Fumio Endo, Kimitoshi Nakamura
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by the deficiency of glucocerebrosidase enzyme activity. Clinical phenotypes of GD are categorized into three groups: (i) non-neuronopathic GD (type 1), (ii) acute neuronopathic GD (type 2) and (iii) subacute neuronopathic GD (type 3). The high-risk screening of neuronopathic GD has been performed using an enzymatic assay on the dried blood spot (DBS) samples. We enrolled a total of 102 individuals (47 females, 55 males; 0-57 years old; median age 10...
March 30, 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29595653/type-i-gaucher-disease-with-bullous-pemphigoid-and-parkinson-disease-a-case-report
#19
Damien Le Peillet, Virginie Prendki, Véronique Trombert, Emmanuel Laffitte, Frédéric Assal, Jean Luc Reny, Christine Serratrice
RATIONALE: Gaucher disease (GD) is a rare genetic lysosomal storage disorder inherited in an autosomal recessive pattern. GD is due to the deficiency of a lysosomal enzyme, acid beta-glucosidase (or glucocerebrosidase). Type 1 Gaucher disease (GD1) is characterized by thrombocytopenia, anemia, an enlarged spleen, and liver as well as bone complications (Erlenmeyer flask deformity, osteoporosis, lytic lesions, pathological and vertebral fractures, bone infarcts, and avascular necrosis leading to degenerative arthropathy)...
March 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29579237/acid-ceramidase-inhibition-ameliorates-%C3%AE-synuclein-accumulation-upon-loss-of-gba1-function
#20
Myung Jong Kim, Sohee Jeon, Lena F Burbulla, Dimitri Krainc
GBA1 encodes the lysosomal enzyme β-glucocerebrosidase (GCase) which converts glucosylceramide into ceramide and glucose. Mutations in GBA1 lead to Gaucher's disease and are a major risk factor for Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), synucleinopathies characterized by accumulation of intracellular α-synuclein. In this study, we examined whether decreased ceramide that is observed in GCase-deficient cells contributes to α-synuclein accumulation. We demonstrated that deficiency of GCase leads to a reduction of C18-ceramide species and altered intracellular localization of Rab8a, a small GTPase implicated in secretory autophagy, that contributed to impaired secretion of α-synuclein and accumulation of intracellular α-synuclein...
March 22, 2018: Human Molecular Genetics
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