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https://www.readbyqxmd.com/read/28819579/dual-task-performance-in-gba-parkinson-s-disease
#1
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
#2
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
https://www.readbyqxmd.com/read/28485919/stabilization-of-glucocerebrosidase-by-active-site-occupancy
#3
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
#4
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
#5
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
#6
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
#7
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...
December 19, 2016: 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
#8
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...
December 26, 2016: Joint, Bone, Spine: Revue du Rhumatisme
https://www.readbyqxmd.com/read/28030538/gba-variants-influence-motor-and-non-motor-features-of-parkinson-s-disease
#9
Silvia Jesús, Ismael Huertas, Inmaculada Bernal-Bernal, Marta Bonilla-Toribio, María Teresa Cáceres-Redondo, Laura Vargas-González, Myriam Gómez-Llamas, Fátima Carrillo, Enrique Calderón, Manuel Carballo, Pilar Gómez-Garre, Pablo Mir
The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression...
2016: PloS One
https://www.readbyqxmd.com/read/28011901/efferocytosis-is-impaired-in-gaucher-macrophages
#10
Elma Aflaki, Daniel K Borger, Richard J Grey, Martha Kirby, Stacie Anderson, Grisel Lopez, Ellen Sidransky
Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylceramide-laden macrophages resulting from impaired digestion of aged erythrocytes or apoptotic leukocytes. Studies of macrophages from patients with type 1 Gaucher disease with genotypes N370S/N370S, N370S/L444P or N370S/c.84dupG revealed that Gaucher macrophages have impaired efferocytosis resulting from reduced levels of p67(phox) and Rab7. The decreased Rab7 expression leads to impaired fusion of phagosomes with lysosomes...
April 2017: Haematologica
https://www.readbyqxmd.com/read/27905362/-characteristics-of-parkinson-s-disease-course-in-the-heterozygous-carriage-of-mutations-in-the-glucocerebrosidase-a-gene
#11
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
https://www.readbyqxmd.com/read/27872820/nine-year-experience-in-gaucher-disease-diagnosis-at-the-spanish-reference-center-fundaci%C3%A3-n-jim%C3%A3-nez-d%C3%A3-az
#12
N V Ortiz-Cabrera, J Gallego-Merlo, C Vélez-Monsalve, R de Nicolas, S Fontao Mas, C Ayuso, M J Trujillo-Tiebas
BACKGROUND: Fundación Jiménez Díaz (FJD) is a reference center for genetic diagnosis of Gaucher disease (GD) in Spain. Genetic analyses of acid β-glucosidase (GBA) gene using different techniques were performed to search for new mutations, in addition to those previously and most frequently found in the Spanish population. Additionally, the study of the chitotriosidase (CHIT1) gene was used to assess the inflammatory status of patients in the follow-up of enzyme replacement therapy (ERT)...
December 2016: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/27864021/trio-approach-reveals-higher-risk-of-pd-in-carriers-of-severe-vs-mild-gba-mutations
#13
David Arkadir, Tama Dinur, Stephen Mullin, Atul Mehta, Hagit N Baris, Roy N Alcalay, Ari Zimran
Heterozygote GBA (glucosylceramidase beta) mutations increase the risk of Parkinson's disease (PD). Data based on the measured frequencies of GBA mutated alleles in the healthy population suggest that severe GBA mutations are associated with even higher risk for PD. These data, however, are prone to methodological biases resulting from the rarity of severe mutations and from ethnic-dependent differences in allele frequencies. To overcome these biases, we traced 13 Gaucher disease (GD) patients who were compound heterozygotes for one mild (N370S) and one severe GBA mutation and who reported a parent with PD...
November 12, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27816428/ferritinemia-and-serum-inflammatory-cytokines-in-swedish-adults-with-gaucher-disease-type-1
#14
Fryderyk Lorenz, Ewa Pawłowicz, Monika Klimkowska, Soheir Beshara, Agnes Bulanda Brustad, Aleksander B Skotnicki, Anders Wahlin, Maciej Machaczka
BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden...
October 20, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27777137/autosomal-dominant-parkinson-s-disease-incidence-of-mutations-in-lrrk2-snca-vps35-and-gba-genes-in-brazil
#15
Gabriella de M Abreu, Débora Cristina T Valença, Mário Campos, Camilla P da Silva, João S Pereira, Marco A Araujo Leite, Ana Lucia Rosso, Denise H Nicaretta, Luiz Felipe R Vasconcellos, Delson José da Silva, Marcus V Della Coletta, Jussara M Dos Santos, Andressa P Gonçalves, Cíntia B Santos-Rebouças, Márcia M G Pimentel
INTRODUCTION: Amongst Parkinson's disease (PD) genetic factors, mutations in LRRK2, SNCA, VPS35 and GBA genes are recognized causes of PD. Nonetheless, few genetic screenings have been conducted in families with a history of PD consistent with autosomal dominant inheritance (ADPD), and their relevance to the etiology of PD has been poorly explored in Latin American populations, such as the Brazilian one, with a high degree of admixture. METHODS: In order to assess the contribution of specific mutations in LRRK2, SNCA, VPS35 and GBA genes to ADPD in Brazil, we conducted the first molecular evaluation in a cohort of 141 index cases from families with ADPD...
December 2, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27723713/-characteristics-of-parkinson-s-disease-course-in-the-heterozygous-carriage-of-mutations-in-the-glucocerebrosidase-a-gene
#16
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
https://www.readbyqxmd.com/read/27717005/specifically-neuropathic-gaucher-s-mutations-accelerate-cognitive-decline-in-parkinson-s
#17
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 specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models...
November 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27632223/survival-and-dementia-in-gba-associated-parkinson-s-disease-the-mutation-matters
#18
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...
November 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27598312/design-and-synthesis-of-potent-quinazolines-as-selective-%C3%AE-glucocerebrosidase-modulators
#19
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
https://www.readbyqxmd.com/read/27539639/parkinson-disease-linked-gba-mutation-effects-reversed-by-molecular-chaperones-in-human-cell-and-fly-models
#20
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...
August 19, 2016: Scientific Reports
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