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[PMID]:28592445
[Au] Autor:Liao HC; Spacil Z; Ghomashchi F; Escolar ML; Kurtzberg J; Orsini JJ; Turecek F; Scott CR; Gelb MH
[Ad] Endereço:Department of Chemistry, University of Washington, Seattle, WA.
[Ti] Título:Lymphocyte Galactocerebrosidase Activity by LC-MS/MS for Post-Newborn Screening Evaluation of Krabbe Disease.
[So] Source:Clin Chem;63(8):1363-1369, 2017 Aug.
[Is] ISSN:1530-8561
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Deficiency of the lysosomal enzyme galactosylcerebrosidase (GALC) causes Krabbe disease. Newborn screening for Krabbe disease is ongoing, but improved methods for follow-up analysis of screen-positive babies are needed to better advise families and to optimize treatment. We report a new assay for the enzymatic activity of GALC in lymphocytes. METHODS: T lymphocytes were isolated from venous blood by magnetic bead technology. The assay used a close structural analog of the natural substrate and LC-MS/MS to quantify the amount of product with the aid of a chemically identical internal standard. RESULTS: The analytical range of the assay (ratio of assay response for the QC high standard to that from all non-enzymatic-dependent processes) was 20-fold greater than that for the conventional radiometric GALC assay. The LC-MS/MS could distinguish cells that were null in GALC from those that contained traces of active enzyme (down to 0.3% of normal). There was a good correlation between the level of residual GALC activity in lymphocytes and the severity of Krabbe disease. CONCLUSIONS: The new assay can measure small amounts of residual GALC activity in leukocytes with high accuracy compared to previous assays and can contribute, along with genotyping, biomarker analysis, and neurological imaging, a better plan for post-newborn screening follow-up for Krabbe disease.
[Mh] Termos MeSH primário: Galactosilceramidase/metabolismo
Leucodistrofia de Células Globoides/enzimologia
Triagem Neonatal/métodos
Linfócitos T/enzimologia
[Mh] Termos MeSH secundário: Criança
Cromatografia Líquida
Galactosilceramidase/análise
Galactosilceramidase/deficiência
Seres Humanos
Recém-Nascido
Leucodistrofia de Células Globoides/metabolismo
Linfócitos T/metabolismo
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1373/clinchem.2016.264952


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[PMID]:28103109
[Au] Autor:Luddi A; Gori M; Crifasi L; Marrocco C; Belmonte G; Costantino-Ceccarini E; Piomboni P
[Ad] Endereço:a Department of Molecular and Developmental Medicine , University of Siena , Siena, Italy.
[Ti] Título:Impaired spermatogenesis in the twitcher mouse: A morphological evaluation from the seminiferous tubules to epididymal transit.
[So] Source:Syst Biol Reprod Med;63(2):77-85, 2017 Apr.
[Is] ISSN:1939-6376
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Spermatogenesis is a complex process of proliferation and differentiation during male germ cell development whereby undifferentiated spermatogonial germ cells evolve into maturing spermatozoa. In this developmental process the interactions between different cell types are finely regulated, hence any disruption in these relationships leads to male infertility. The twitcher mouse, the murine model of Krabbe disease, is characterized by deficiency of galactosylceramidase, an enzyme also involved in the metabolism of the galactosyl-alkyl-acyl-glycerol, the precursor of sulfogalactosyl-alkyl-acyl-glycerol, the most abundant glycolipid in spermatozoa. Twitcher mice are sterile due to alterations of spermatogenesis resulting in the production of spermatozoa with abnormally swollen acrosomes and bent flagella, mainly at the midpiece-principal piece junction. The current study employs light, fluorescence, and electron microscopy to examine the defective spermiogenesis leading to the morphological abnormalities of mature sperm. This study reveals that alterations in germ cell development can be initially detected at the stage VIII and IX of spermatogenesis. The disrupted spermatogenetic process leads to a reduced number of elongating spermatids and spermatozoa in these mutant animals. Electron microscopy analysis demonstrates major acrosomal and chromatin condensation defects in the mutants. In addition, in twitcher mice, the epididymal architecture is impaired, with stereocilia of caput and corpus broken, detached and completely spread out into the lumen. These findings indicate that seminolipid expression is crucial for proper development of spermatocytes and spermatids and for their normal differentiation into mature spermatozoa. ABBREVIATIONS: GALC: galactosylceramidase; GalAAG: galactosyl-alkyl-acyl-glycerol; SGalAAG: sulfogalactosylalkylacylglycerol; PND: postnatal day; PAS: periodic acid-Schiff stain; TEM: transmission electron microscopy; SEM: scanning electron microscopy; PFA: paraformaldheyde.
[Mh] Termos MeSH primário: Epididimo/ultraestrutura
Infertilidade Masculina/patologia
Túbulos Seminíferos/ultraestrutura
Espermatogênese
Espermatozoides/ultraestrutura
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Epididimo/enzimologia
Galactosilceramidase/genética
Galactosilceramidase/metabolismo
Predisposição Genética para Doença
Infertilidade Masculina/enzimologia
Infertilidade Masculina/genética
Infertilidade Masculina/fisiopatologia
Leucodistrofia de Células Globoides/complicações
Leucodistrofia de Células Globoides/enzimologia
Leucodistrofia de Células Globoides/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Microscopia Eletrônica de Varredura
Microscopia Eletrônica de Transmissão
Fenótipo
Túbulos Seminíferos/enzimologia
Espermatozoides/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170120
[St] Status:MEDLINE
[do] DOI:10.1080/19396368.2016.1271918


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[PMID]:28000364
[Au] Autor:Marques AR; Willems LI; Herrera Moro D; Florea BI; Scheij S; Ottenhoff R; van Roomen CP; Verhoek M; Nelson JK; Kallemeijn WW; Biela-Banas A; Martin OR; Cachón-González MB; Kim NN; Cox TM; Boot RG; Overkleeft HS; Aerts JM
[Ad] Endereço:Department of Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
[Ti] Título:A Specific Activity-Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease.
[So] Source:Chembiochem;18(4):402-412, 2017 Feb 16.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Galactosylceramidase (GALC) is the lysosomal ß-galactosidase responsible for the hydrolysis of galactosylceramide. Inherited deficiency in GALC causes Krabbe disease, a devastating neurological disorder characterized by accumulation of galactosylceramide and its deacylated counterpart, the toxic sphingoid base galactosylsphingosine (psychosine). We report the design and application of a fluorescently tagged activity-based probe (ABP) for the sensitive and specific labeling of active GALC molecules from various species. The probe consists of a ß-galactopyranose-configured cyclophellitol-epoxide core, conferring specificity for GALC, equipped with a BODIPY fluorophore at C6 that allows visualization of active enzyme in cells and tissues. Detection of residual GALC in patient fibroblasts holds great promise for laboratory diagnosis of Krabbe disease. We further describe a procedure for in situ imaging of active GALC in murine brain by intra-cerebroventricular infusion of the ABP. In conclusion, this GALC-specific ABP should find broad applications in diagnosis, drug development, and evaluation of therapy for Krabbe disease.
[Mh] Termos MeSH primário: Galactosilceramidase/genética
Galactosilceramidase/metabolismo
Leucodistrofia de Células Globoides/enzimologia
Sondas Moleculares
[Mh] Termos MeSH secundário: Deficiências Nutricionais/enzimologia
Deficiências Nutricionais/genética
Galactosilceramidase/antagonistas & inibidores
Leucodistrofia de Células Globoides/diagnóstico
Leucodistrofia de Células Globoides/genética
Doenças por Armazenamento dos Lisossomos/enzimologia
Doenças por Armazenamento dos Lisossomos/genética
Estrutura Molecular
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Molecular Probes); EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201600561


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[PMID]:27721144
[Au] Autor:Goddard-Borger ED; Tysoe C; Withers SG
[Ad] Endereço:Centre for High-Throughput Biology, Michael Smith Laboratories, 185 East Mall, Vancouver, British Columbia, V6T 1Z4, Canada; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T 1Z1 Canada.
[Ti] Título:Glycosynthase mediated synthesis of psychosine.
[So] Source:Carbohydr Res;435:97-99, 2016 Nov 29.
[Is] ISSN:1873-426X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Globoid cell leukodystrophy (GCL), or Krabbe disease, is a lysosomal storage disorder characterized by a deficiency in galactosylceramidase (GALC), which hydrolyses galactosylceramide and galactosylsphingosine (psychosine). Early detection of GCL in newborns is essential for timely therapeutic intervention and could be achieved by testing infant blood samples with isotopically labeled lysosmal enzyme substrates and mass spectrometry. While isotopically labeled psychosine would be a useful tool for the early diagnosis of GCL, its synthesis is lengthy and expensive. To obviate this problem we developed a one-step chemoenzymatic synthesis of psychosine using a glycosynthase mutant of the Rhodococcus equi endogalactosylceramidase (EGALC), α-D-galactopyranosyl fluoride and sphingosine.
[Mh] Termos MeSH primário: Galactosilceramidase/genética
Monossacarídeos/química
Psicosina/biossíntese
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Diagnóstico Precoce
Galactosilceramidase/metabolismo
Seres Humanos
Recém-Nascido
Leucodistrofia de Células Globoides/diagnóstico
Mutação
Rhodococcus equi/enzimologia
Rhodococcus equi/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Monosaccharides); 0 (galactopyranosyl fluoride); 2238-90-6 (Psychosine); EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170227
[Lr] Data última revisão:
170227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161011
[St] Status:MEDLINE


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[PMID]:27638614
[Au] Autor:Marshall MS; Bongarzone ER
[Ad] Endereço:Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois. mmarsh22@uic.edu.
[Ti] Título:Beyond Krabbe's disease: The potential contribution of galactosylceramidase deficiency to neuronal vulnerability in late-onset synucleinopathies.
[So] Source:J Neurosci Res;94(11):1328-32, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:New insights into the pathophysiological mechanisms behind late-onset neurodegenerative diseases have come from unexpected sources in recent years. Specifically, the group of inherited metabolic disorders known as lysosomal storage diseases that most commonly affect infants has been found to have surprising similarities with adult neurodegenerative disorders. Most notable has been the identification of Gaucher's disease as a comorbidity for Parkinson's disease. Prompted by the recent identification of neuronal aggregates of α-synuclein in another lysosomal storage disease, Krabbe's disease, we propose the idea that a similar connection exists between adult synucleinopathies and Krabbe's. Similarities between the two diseases, including the pattern of α-synuclein aggregation in the brain of the twitcher mouse (the authentic murine model of Krabbe's disease), changes to lipid membrane dynamics, and possible dysfunction in synaptic function and macroautophagy, underscore a link between Krabbe's disease and late-onset synucleinopathies. Silent GALC mutations may even constitute a risk factor for the development of Parkinson's in certain patients. More research is required to identify definitively any link and the validity of this hypothesis, but such a connection would prove invaluable for developing novel therapeutic targets for Parkinson's based on our current understanding of Krabbe's disease and for establishing new biomarkers for the identification of at-risk patients. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Encéfalo/patologia
Leucodistrofia de Células Globoides
Neurônios/patologia
alfa-Sinucleína/metabolismo
[Mh] Termos MeSH secundário: Animais
Estruturas da Membrana Celular/patologia
Galactosilceramidase/genética
Galactosilceramidase/metabolismo
Predisposição Genética para Doença
Seres Humanos
Leucodistrofia de Células Globoides/genética
Leucodistrofia de Células Globoides/metabolismo
Leucodistrofia de Células Globoides/patologia
Lipídeos/fisiologia
Mutação/genética
Neurônios/metabolismo
Agregados Proteicos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipids); 0 (Protein Aggregates); 0 (alpha-Synuclein); EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/jnr.23751


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[PMID]:27638612
[Au] Autor:Ricca A; Gritti A
[Ad] Endereço:San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
[Ti] Título:Perspective on innovative therapies for globoid cell leukodystrophy.
[So] Source:J Neurosci Res;94(11):1304-17, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a lysosomal storage disorder resulting from deficiency of the lysosomal hydrolase galactosylceramidase. The infantile forms are characterized by a unique relentless and aggressive progression with a wide range of neurological symptoms and complications. Here we review and discuss the basic concepts and the novel mechanisms identified as key contributors to the peculiar GLD pathology, highlighting their therapeutic implications. Then, we evaluate evidence from extensive experimental studies on GLD animal models that have highlighted fundamental requirements to obtain substantial therapeutic benefit, including early and timely intervention, high levels of enzymatic reconstitution, and global targeting of affected tissues. Continuous efforts in understanding GLD pathophysiology, the interplay between various therapies, and the mechanisms of disease correction upon intervention may allow advancing research with innovative approaches and prioritizing treatment strategies to develop more efficacious treatments. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Leucodistrofia de Células Globoides/terapia
Terapias em Estudo/métodos
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Galactosilceramidase/deficiência
Galactosilceramidase/genética
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/jnr.23752


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[PMID]:27638609
[Au] Autor:Luddi A; Crifasi L; Capaldo A; Piomboni P; Costantino-Ceccarini E
[Ad] Endereço:Department of Molecular and Developmental Medicine, Siena University, Siena, Italy. luddi@unisi.it.
[Ti] Título:Suppression of galactocerebrosidase premature termination codon and rescue of galactocerebrosidase activity in twitcher cells.
[So] Source:J Neurosci Res;94(11):1273-83, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Krabbe's disease (KD) is a degenerative lysosomal storage disease resulting from deficiency of ß-galactocerebrosidase activity. Over 100 mutations are known to cause the disease, and these usually occur in compound heterozygote patterns. In affected patients, nonsense mutations leading to a nonfunctional enzyme are often found associated with other mutations. The twitcher mouse is a naturally occurring model of KD, containing in ß-galactocerebrosidase a premature stop codon, W339X. Recent studies have shown that selected compounds may induce the ribosomal bypass of premature stop codons without affecting the normal termination codons. The rescue of ß-galactocerebrosidase activity induced by treatment with premature termination codon (PTC) 124, a well-characterized compound known to induce ribosomal read-through, was investigated on oligodendrocytes prepared from twitcher mice and on human fibroblasts from patients bearing nonsense mutations. The effectiveness of the nonsense-mediated mRNA decay (NMD) inhibitor 1 (NMDI1), a newly identified inhibitor of NMD, was also tested. Incubation of these cell lines with PTC124 and NMDI1 increased the levels of mRNA and rescued galactocerebrosidase enzymatic activity in a dose-dependent manner. The low but sustained expression of ß-galactocerebrosidase in oligodendrocytes was sufficient to improve the morphology of the differentiated cells. Our in vitro approach provides the basis for further investigation of ribosomal read-through as an alternative therapeutic strategy to ameliorate the quality of life in selected KD patients. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Códon de Terminação/genética
Galactosilceramidase/deficiência
Galactosilceramidase/genética
Galactosilceramidas/metabolismo
Leucodistrofia de Células Globoides/patologia
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Linhagem Celular Transformada
Códon de Terminação/metabolismo
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Fibroblastos/efeitos dos fármacos
Fibroblastos/enzimologia
Galactosilceramidas/genética
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Mutantes
Degradação do RNAm Mediada por Códon sem Sentido/efeitos dos fármacos
Oligodendroglia/efeitos dos fármacos
Oligodendroglia/enzimologia
Oxidiazóis/farmacologia
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon, Terminator); 0 (Galactosylceramides); 0 (Oxadiazoles); 0 (RNA, Messenger); 0 (galactocerebroside); EC 3.2.1.46 (Galactosylceramidase); K16AME9I3V (ataluren)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/jnr.23790


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[PMID]:27638608
[Au] Autor:Sands SA; LeVine SM
[Ad] Endereço:Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
[Ti] Título:Substrate reduction therapy for Krabbe's disease.
[So] Source:J Neurosci Res;94(11):1261-72, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose-sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used. Unfortunately, an inhibitor for the final step of galactosylceramide biosynthesis, i.e., UDP glycosyltransferase 8 (a.k.a. UDP-galactose ceramide galactosyltransferase), has not been found. Approaches that inhibit an earlier biosynthetic step or that lessen the substrate burden by other means, such as genetic manipulations, have been tested in the twitcher mouse model of KD. Either as a stand-alone therapy or in combination with other approaches, SRT slowed the disease course, indicating that this approach has potential therapeutic value. For instance, in individuals with adult-onset disease, SRT theoretically could lessen the production of substrates so that residual enzymatic activity could adequately manage the lower substrate burden. In more severe forms of disease, SRT theoretically could be part of a combination therapy. However, SRT has the potential to impair normal function by reducing the synthesis of galactosylceramide to levels that impede myelin function, or SRT could have other deleterious effects. Thus, multiple issues need to be resolved before this approach is ready for testing in humans. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/uso terapêutico
Galactosilceramidase/deficiência
Leucodistrofia de Células Globoides/enzimologia
Leucodistrofia de Células Globoides/terapia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/jnr.23791


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[PMID]:27638606
[Au] Autor:Jang DS; Ye W; Guimei T; Solomon M; Southall N; Hu X; Marugan J; Ferrer M; Maegawa GH
[Ad] Endereço:Department of Pediatrics, University of Florida, Gainesville, Florida.
[Ti] Título:Cell-based high-throughput screening identifies galactocerebrosidase enhancers as potential small-molecule therapies for Krabbe's disease.
[So] Source:J Neurosci Res;94(11):1231-45, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Krabbe's disease, also known as globoid cell leukodystrophy (GLD), is a lysosomal storage disease caused by the deficiency of the lysosomal enzyme ß-galactocerebrosidase (GALC), resulting in severe neurological manifestations related to demyelination secondary to elevated galactosylsphingosine (psychosine) with its subsequent cytotoxicity. The only available treatment is hematopoietic stem cell transplantation, which delays disease onset but does not prevent long-term neurological manifestations. This article describes the identification of small molecules that enhance mutant GALC activity, identified by quantitative cell-based high-throughput screening (qHTS). Using a specific neurologically relevant murine cell line (145M-Twi) modified to express common human hGALC-G270D mutant, we were able to detect GALC activity in a 1,536-well microplate format. The qHTS of approximately 46,000 compounds identified three small molecules that showed significant enhancements of residual mutant GALC activity in primary cell lines from GLD patients. These compounds were shown to increase the levels of GALC-G270D mutant in the lysosomal compartment. In kinetic assessments, these small molecules failed to disturb the GALC kinetic profile under acidic conditions, which is highly desirable for folding-assisting molecules operating in the endoplasmic reticulum and not affecting GALC catalytic properties in the lysosomal compartment. In addition, these small molecules rescued the decreased GALC activity at neutral pH and partially stabilized GALC under heat-denaturating conditions. These drug-like compounds can be used as the starting point to develop novel small-molecule agents to treat the progressive neurodegenerative course of GLD. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Galactosilceramidase/metabolismo
Ensaios de Triagem em Larga Escala/métodos
Leucodistrofia de Células Globoides/tratamento farmacológico
Bibliotecas de Moléculas Pequenas/química
[Mh] Termos MeSH secundário: Células Cultivadas
Relação Dose-Resposta a Droga
Fibroblastos/enzimologia
Galactosilceramidase/química
Galactosilceramidase/genética
Seres Humanos
Leucodistrofia de Células Globoides/patologia
Mutação/genética
Polilisina/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Small Molecule Libraries); 25104-18-1 (Polylysine); EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/jnr.23875


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[PMID]:27638604
[Au] Autor:Spratley SJ; Deane JE
[Ad] Endereço:Cambridge Institute for Medical Research, Department of Pathology University of Cambridge, Cambridge, United Kingdom.
[Ti] Título:New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones.
[So] Source:J Neurosci Res;94(11):1203-19, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Missense mutations in the lysosomal hydrolase ß-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small-molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Leucodistrofia de Células Globoides/tratamento farmacológico
Chaperonas Moleculares/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Terapia de Reposição de Enzimas
Galactosilceramidase/genética
Galactosilceramidase/metabolismo
Seres Humanos
Leucodistrofia de Células Globoides/genética
Chaperonas Moleculares/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Molecular Chaperones); EC 3.2.1.46 (Galactosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE
[do] DOI:10.1002/jnr.23762



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