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Rainer von Coelln, Lisa M Shulman
PURPOSE OF REVIEW: Recent studies on clinical, genetic and pathological heterogeneity of Parkinson disease have renewed the old debate whether we should think of Parkinson disease as one disease with variations, or as a group of independent diseases that happen to present with similar phenotypes. Here, we provide an overview of where the debate is coming from, and how recent findings in clinical subtyping, genetics and clinico-pathological correlation have shaped this controversy over the last few years...
October 5, 2016: Current Opinion in Neurology
Tamara Shiner, Anat Mirelman, Mali Gana Weisz, Anat Bar-Shira, Elissa Ash, Ron Cialic, Naomi Nevler, Tanya Gurevich, Noa Bregman, Avi Orr-Urtreger, Nir Giladi
Importance: Mutations in the glucocerebrosidase (GBA) gene are a risk factor for the development of dementia with Lewy bodies (DLB). These mutations are common among Ashkenazi Jews (AJ) and appear to have an effect on the natural history of the disease. Objectives: To evaluate the clinical and genetic characteristics of an AJ cohort of patients diagnosed with DLB, assess the association of phenotype of DLB with GBA mutations, and explore the effects of these mutations on the clinical course of the disease...
October 10, 2016: JAMA Neurology
O A Gan'kina, E E Vasenina, O S Levin, E Yu Fedotova, S N Illarioshkin
Parkinson's disease (PD) is a common neurodegenerative disease. Literature sources indicate the association of PD and mutations in the glucocerebrosidase A (GBA) gene. According to our study, the frequency of the two most common mutations in the GBA gene, N370S and L444P, is 1.85%. Mutation carriers have slower progression of motor symptoms, but are more likely to develop drug-induced motor fluctuations and dyskinesia. In carriers of GBA mutations, the severity of cognitive impairment corresponds to age-matched patients without mutations...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Ganqiang Liu, Brendon Boot, Joseph J Locascio, Iris E Jansen, Sophie Winder-Rhodes, Shirley Eberly, Alexis Elbaz, Alexis Brice, Bernard Ravina, Jacobus J van Hilten, Florence Cormier-Dequaire, Jean-Christophe Corvol, Roger A Barker, Peter Heutink, Johan Marinus, Caroline H Williams-Gray, Clemens R Scherzer
OBJECTIVE: We hypothesized that mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes will be associated with aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, while mutations associated with non-neuropathic GD will confer intermediate progression rates. METHODS: 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median 4.1) from seven cohorts were analyzed...
September 22, 2016: Annals of Neurology
Gian D Pal, Deborah Hall, Bichun Ouyang, Jessica Phelps, Roy Alcalay, Michael W Pauciulo, William C Nichols, Lorraine Clark, Helen Mejia-Santana, Lucia Blasucci, Christopher G Goetz, Cynthia Comella, Amy Colcher, Ziv Gan-Or, Guy A Rouleau, Karen Marder
OBJECTIVE: In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. METHODS: Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years...
September 2016: Movement Disorders Clinical Practice
Hisako Akiyama, Kazuki Nakajima, Yoshiyuki Itoh, Tomoko Sayano, Yoko Ohashi, Yoshiki Yamaguchi, Peter Greimel, Yoshio Hirabayashi
To date, sterylglucosides have been reported to be present in various fungi, plants, and animals. In bacteria, such as Helicobacter pylori, proton NMR spectral analysis of isolated cholesterylglucoside (GlcChol) demonstrated the presence of an α-glucosidic linkage. By contrast in animals, no detailed structural analysis of GlcChol has been reported, in part because animal-derived samples contain a high abundance of glucosylceramides/galactosylceramides, which exhibit highly similar chromatographic behavior to GlcChol...
October 3, 2016: Journal of Lipid Research
Shinichiro Yoshida, Jun Kido, Shirou Matsumoto, Ken Momosaki, Hiroshi Mitsubuchi, Tomoyuki Shimazu, Keishin Sugawara, Fumio Endo, Kimitoshi Nakamura
In the prenatal diagnosis of Gaucher disease (GD), glucocerebrosidase (GBA) activity is measured with fetal cells, and gene analysis is performed when pathogenic mutations in GBA are identified in advance. Herein is described prenatal diagnosis in a family in which two children had GD. Although prior genetic information for this GD family was not obtained, next-generation sequencing (NGS) was carried out for this family because immediate prenatal diagnosis was necessary. Three mutations were identified in this GD family...
September 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
Victoria Mallett, Jay P Ross, Roy N Alcalay, Amirthagowri Ambalavanan, Ellen Sidransky, Patrick A Dion, Guy A Rouleau, Ziv Gan-Or
The lysosomal enzyme glucocerebrosidase (GCase), encoded by GBA, has an important role in Parkinson disease (PD). GBA mutation carriers have an increased risk for PD, earlier age at onset, faster progression, and various nonmotor symptoms including cognitive decline, REM sleep behavior disorder, hyposmia, and autonomic dysfunction.(1) Furthermore, GCase enzymatic activity is reduced in the peripheral blood(2) and brain(3) of noncarrier, sporadic PD patients. Biallelic GBA mutations, which have been classified as "severe" or "mild," may cause Gaucher disease (GD), a lysosomal storage disorder...
October 2016: Neurology. Genetics
Gertjan Kramer, Wouter Wegdam, Wilma Donker-Koopman, Roelof Ottenhoff, Paulo Gaspar, Marri Verhoek, Jessica Nelson, Tanit Gabriel, Wouter Kallemeijn, Rolf G Boot, Jon D Laman, Johannes P C Vissers, Timothy Cox, Elena Pavlova, Mary Teresa Moran, Johannes M Aerts, Marco van Eijk
Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities...
September 2016: FEBS Open Bio
Roberto Cilia, Sara Tunesi, Giorgio Marotta, Emanuele Cereda, Chiara Siri, Silvana Tesei, Anna L Zecchinelli, Margherita Canesi, Claudio B Mariani, Nicoletta Meucci, Giorgio Sacilotto, Michela Zini, Michela Barichella, Corrado Magnani, Stefano Duga, Rosanna Asselta, Giulia Soldà, Agostino Seresini, Manuela Seia, Gianni Pezzoli, Stefano Goldwurm
OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group...
September 15, 2016: Annals of Neurology
Yvette C Wong, Dimitri Krainc
Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss-of-function mutations in the GTP-binding protein type A1 (GBA1) gene encoding the lysosomal hydrolase β-glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α-synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β-glucocerebrosidase activity...
September 13, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Alen Sevšek, Maša Čelan, Bibi Erjavec, Linda Quarles van Ufford, Javier Sastre Toraño, Ed E Moret, Roland J Pieters, Nathaniel I Martin
A series of bicyclic isourea derivatives were prepared from 1-deoxynojirimycin using a concise synthetic protocol proceeding via a guanidino intermediate. Inhibition assays with a panel of glycosidases revealed that these deoxynojirimycin-derived bicyclic isoureas display very potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range.
October 7, 2016: Organic & Biomolecular Chemistry
Jianbin Zheng, Long Chen, Michael Schwake, Richard B Silverman, Dimitri Krainc
Gaucher's disease is a common genetic disease caused by mutations in the β-glucocerebrosidase (GBA1) gene that have been also linked to increased risk of Parkinson's disease and Lewy body dementia. Stabilization of misfolded mutant β-glucocerebrosidase (GCase) represents an important therapeutic strategy in synucleinopathies. Here we report a novel class of GCase quinazoline inhibitors, obtained in a high throughput screening, with moderate potency against wild-type GCase. Rational design and a SAR study of this class of compounds led to a new series of quinazoline derivatives with single-digit nanomolar potency...
September 22, 2016: Journal of Medicinal Chemistry
Naohiro Hashimoto, Ikiru Matsumoto, Hiromasa Takahashi, Hitomi Ashikawa, Hiroyuki Nakamura, Toshihiko Murayama
Sphingolipids such as sphingomyelin and glycosphingolipids (GSLs) derived from glucosylceramide (GlcCer), in addition to cholesterol, accumulate in cells/neurons in Niemann-Pick disease type C (NPC). The activities of acid sphingomyelinase and lysosomal glucocerebrosidase (GCase), which degrade sphingomyelin and GlcCer, respectively, are down-regulated in NPC cells, however, changes in GlcCer synthase activity have not yet been elucidated. We herein demonstrated for the first time that GlcCer synthase activity for the fluorescent ceramide, 4-nitrobenzo-2-oxa-1,3-diazole-labeled C6-ceramide (NBD-ceramide) increased in intact NPC1((-/-)) cells and cell lysates without affecting the protein levels...
November 2016: Neuropharmacology
Alvaro Sanchez-Martinez, Michelle Beavan, Matthew E Gegg, Kai-Yin Chau, Alexander J Whitworth, Anthony H V Schapira
GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD...
2016: Scientific Reports
Ruggero Ferrazza, Susanna Cogo, Heather Melrose, Luigi Bubacco, Elisa Greggio, Graziano Guella, Laura Civiero, Nicoletta Plotegher
Mutations in LRRK2 gene cause inherited Parkinson's disease (PD) and variations around LRRK2 act as risk factor for disease. Similar to sporadic disease, LRRK2-linked cases show late onset and, typically, the presence of proteinaceous inclusions named Lewy bodies (LBs) in neurons. Recently, defects on ceramide (Cer) metabolism have been recognized in PD. In particular, heterozygous mutations in the gene encoding for glucocerebrosidase (GBA1), a lysosomal enzyme converting glucosyl-ceramides (Glc-Cer) into Cer, increase the risk of developing PD...
September 23, 2016: Biochemical and Biophysical Research Communications
Jinlong Jian, Shuai Zhao, Qing-Yun Tian, Helen Liu, Yunpeng Zhao, Wen-Chi Chen, Gabriele Grunig, Paola A Torres, Betty C Wang, Bai Zeng, Gregory Pastores, Wei Tang, Ying Sun, Gregory A Grabowski, Max Xiangtian Kong, Guilin Wang, Ying Chen, Fengxia Liang, Herman S Overkleeft, Rachel Saunders-Pullman, Gerald L Chan, Chuan-Ju Liu
BACKGROUND: Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD. METHODS: Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples...
September 2016: EBioMedicine
Neha Mahajan, Russell Brynes, Shoji Yano
Extra-osseous masses are rarely seen in Gaucher disease. Here we present a case of a 30-year-old patient with Gaucher disease type 3, receiving β-glucocerebrosidase enzyme replacement therapy, who presented with slowly enlarging masses along her back. There was no osseous extension seen on imaging. Biopsy of the mass ultimately showed extensive soft tissue infiltration by Gaucher cells. No other cases of soft-tissue masses of this extent have been described in the literature, and therefore management remains unclear...
November 2016: Journal of Inherited Metabolic Disease
Nelly Reihani, Jean-Benoit Arlet, Michael Dussiot, Thierry Billette de Villemeur, Nadia Belmatoug, Christian Rose, Yves Colin-Aronovicz, Olivier Hermine, Caroline Le Van Kim, Melanie Franco
Gaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34(+) cells of patients and controls...
July 28, 2016: Haematologica
Fredj Ben Bdira, Jianbing Jiang, Wouter Kallemeijn, Annett de Haan, Bogdan I Florea, Boris Bleijlevens, Rolf Boot, Herman S Overkleeft, Johannes M Aerts, Marcellus Ubbink
Small compound active site interactors receive considerable attention for their ability to positively influence the fold of glycosidases. Endoglycoceramidase II (EGCII) from Rhodococcus sp. is an endo-β-glucosidase releasing the complete glycan from ceramide in glycosphingolipids. Cleavage of the β-glycosidic linkage between glucose and ceramide is also catalyzed by glucocerebrosidase (GBA), the exo-β-glucosidase deficient in Gaucher disease. We demonstrate that established β-glucoside-configured cyclophellitol-type activity-based probes (ABPs) for GBA also are effective, mechanism-based, and irreversible inhibitors of EGCII...
August 30, 2016: Biochemistry
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