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  1 / 282 MEDLINE  
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[PMID]:28847804
[Au] Autor:Taguchi YV; Liu J; Ruan J; Pacheco J; Zhang X; Abbasi J; Keutzer J; Mistry PK; Chandra SS
[Ad] Endereço:Department of Cell Biology.
[Ti] Título:Glucosylsphingosine Promotes α-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease.
[So] Source:J Neurosci;37(40):9617-9631, 2017 Oct 04.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucocerebrosidase 1 ( ) mutations responsible for Gaucher disease (GD) are the most common genetic risk factor for Parkinson's disease (PD). Although the genetic link between GD and PD is well established, the underlying molecular mechanism(s) are not well understood. We propose that glucosylsphingosine, a sphingolipid accumulating in GD, mediates PD pathology in -associated PD. We show that, whereas GD-related sphingolipids (glucosylceramide, glucosylsphingosine, sphingosine, sphingosine-1-phosphate) promote α-synuclein aggregation , glucosylsphingosine triggers the formation of oligomeric α-synuclein species capable of templating in human cells and neurons. Using newly generated GD/PD mouse lines of either sex [ mutant (N370S, L444P, KO) crossed to α-synuclein transgenics], we show that mutations predispose to PD through a loss-of-function mechanism. We further demonstrate that glucosylsphingosine specifically accumulates in young GD/PD mouse brain. With age, brains exhibit glucosylceramide accumulations colocalized with α-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of α-synuclein, increasing PD risk in GD patients and carriers. Parkinson's disease (PD) is a prevalent neurodegenerative disorder in the aging population. Glucocerebrosidase 1 mutations, which cause Gaucher disease, are the most common genetic risk factor for PD, underscoring the importance of delineating the mechanisms underlying mutant -associated PD. We show that lipids accumulating in Gaucher disease, especially glucosylsphingosine, play a key role in PD pathology in the brain. These data indicate that ASAH1 (acid ceramidase 1) and GBA2 (glucocerebrosidase 2) enzymes that mediate glucosylsphingosine production and metabolism are attractive therapeutic targets for treating mutant -associated PD.
[Mh] Termos MeSH primário: Glucosilceramidase/biossíntese
Mutação/fisiologia
Doença de Parkinson/metabolismo
Psicosina/análogos & derivados
alfa-Sinucleína/biossíntese
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Encéfalo/patologia
Feminino
Glucosilceramidase/genética
Células HEK293
Seres Humanos
Masculino
Camundongos
Camundongos Transgênicos
Doença de Parkinson/genética
Doença de Parkinson/patologia
Psicosina/biossíntese
Psicosina/genética
alfa-Sinucleína/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (alpha-Synuclein); 2238-90-6 (Psychosine); 52050-17-6 (sphingosyl beta-glucoside); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1525-17.2017


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[PMID]:28531236
[Au] Autor:D'Auria L; Reiter C; Ward E; Moyano AL; Marshall MS; Nguyen D; Scesa G; Hauck Z; van Breemen R; Givogri MI; Bongarzone ER
[Ad] Endereço:Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, Chicago, Illinois, United States of America.
[Ti] Título:Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe's disease.
[So] Source:PLoS One;12(5):e0178103, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In prior studies, our laboratory showed that psychosine accumulates and disrupts lipid rafts in brain membranes of Krabbe's disease. A model of lipid raft disruption helped explaining psychosine's effects on several signaling pathways important for oligodendrocyte survival and differentiation but provided more limited insight in how this sphingolipid caused demyelination. Here, we have studied how this cationic inverted coned lipid affects the fluidity, stability and structure of myelin and plasma membranes. Using a combination of cutting-edge imaging techniques in non-myelinating (red blood cell), and myelinating (oligodendrocyte) cell models, we show that psychosine is sufficient to disrupt sphingomyelin-enriched domains, increases the rigidity of localized areas in the plasma membrane, and promotes the shedding of membranous microvesicles. The same physicochemical and structural changes were measured in myelin membranes purified from the mutant mouse Twitcher, a model for Krabbe's disease. Areas of higher rigidity were measured in Twitcher myelin and correlated with higher levels of psychosine and of myelin microvesiculation. These results expand our previous analyses and support, for the first time a pathogenic mechanism where psychosine's toxicity in Krabbe disease involves deregulation of cell signaling not only by disruption of membrane rafts, but also by direct local destabilization and fragmentation of the membrane through microvesiculation. This model of membrane disruption may be fundamental to introduce focal weak points in the myelin sheath, and consequent diffuse demyelination in this leukodystrophy, with possible commonality to other demyelinating disorders.
[Mh] Termos MeSH primário: Micropartículas Derivadas de Células/metabolismo
Leucodistrofia de Células Globoides/metabolismo
Bainha de Mielina/metabolismo
Oligodendroglia/citologia
Psicosina/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Modelos Animais de Doenças
Feminino
Seres Humanos
Masculino
Microdomínios da Membrana
Camundongos
Bainha de Mielina/química
Oligodendroglia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
2238-90-6 (Psychosine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178103


  3 / 282 MEDLINE  
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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


  4 / 282 MEDLINE  
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[PMID]:27638610
[Au] Autor:Avola R; Graziano AC; Pannuzzo G; Alvares E; Cardile V
[Ad] Endereço:Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy.
[Ti] Título:Krabbe's leukodystrophy: Approaches and models in vitro.
[So] Source:J Neurosci Res;94(11):1284-92, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This Review describes some in vitro approaches used to investigate the mechanisms involved in Krabbe's disease, with particular regard to the cellular systems employed to study processes of inflammation, apoptosis, and angiogenesis. The aim was to update the knowledge on the results obtained from in vitro models of this neurodegenerative disorder and provide stimuli for future research. For a long time, the nonavailability of established neural cells has limited the understanding of neuropathogenic mechanisms in Krabbe's leukodystrophy. More recently, the development of new Krabbe's disease cell models has allowed the identification of neurologically relevant pathogenic cascades, including the major role of elevated psychosine levels. Thus, direct and/or indirect roles of psychosine in the release of cytokines, reactive oxygen species, and nitric oxide and in the activation of kinases, caspases, and angiogenic factors results should be clearer. In parallel, it is now understood that the presence of globoid cells precedes oligodendrocyte apoptosis and demyelination. The information described here will help to continue the research on Krabbe's leukodystrophy and on potential new therapeutic approaches for this disease that even today, despite numerous attempts, is without cure. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Leucodistrofia de Células Globoides/metabolismo
Leucodistrofia de Células Globoides/patologia
Psicosina/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/fisiologia
Citocinas/metabolismo
Seres Humanos
Técnicas In Vitro
Inflamação/etiologia
Leucodistrofia de Células Globoides/complicações
Neovascularização Patológica/etiologia
Espécies Reativas de Oxigênio
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cytokines); 0 (Reactive Oxygen Species); 2238-90-6 (Psychosine)
[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.23846


  5 / 282 MEDLINE  
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[PMID]:27638607
[Au] Autor:Del Grosso A; Antonini S; Angella L; Tonazzini I; Signore G; Cecchini M
[Ad] Endereço:NEST, Istituto Nanoscienze-CNR, Pisa, Italy.
[Ti] Título:Lithium improves cell viability in psychosine-treated MO3.13 human oligodendrocyte cell line via autophagy activation.
[So] Source:J Neurosci Res;94(11):1246-60, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Globoid cell leukodystrophy (GLD) is a rare, rapidly progressing childhood leukodystrophy triggered by deficit of the lysosomal enzyme galactosylceramidase (GALC) and characterized by the accumulation of galactosylsphingosine (psychosine; PSY) in the nervous system. PSY is a cytotoxic sphingolipid, which leads to widespread degeneration of oligodendrocytes and Schwann cells, causing demyelination. Here we report on autophagy in the human oligodendrocyte cell line MO3.13 treated with PSY and exploitation of Li as an autophagy modulator to rescue cell viability. We demonstrate that PSY causes upregulation of the autophagic flux at the level of autophagosome and autolysosome formation and LC3-II expression. We show that pretreatment with Li, a drug clinically used to treat bipolar disorders, can further stimulate autophagy, improving cell tolerance to PSY. This Li protective effect is found not to be linked to reduction of PSY-induced oxidative stress and might not stem from a reduction of PSY accumulation. These data provide novel information on the intracellular pathways activated during PSY-induced toxicity and suggest the autophagy pathway as a promising novel therapeutic target for ameliorating the GLD phenotype. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Lítio/farmacologia
Oligodendroglia/efeitos dos fármacos
Psicosina/farmacologia
[Mh] Termos MeSH secundário: Análise de Variância
Anexina A5/metabolismo
Linhagem Celular Transformada
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Seres Humanos
Lactosilceramidas/genética
Lactosilceramidas/metabolismo
Psicosina/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Proteína Sequestossoma-1/metabolismo
Transdução de Sinais/efeitos dos fármacos
Transfecção
Tubulina (Proteína)/genética
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A5); 0 (Lactosylceramides); 0 (Reactive Oxygen Species); 0 (SQSTM1 protein, human); 0 (Sequestosome-1 Protein); 0 (Tubulin); 147336-22-9 (Green Fluorescent Proteins); 2238-90-6 (Psychosine); 73467-80-8 (lactotriaosylceramide); 9FN79X2M3F (Lithium)
[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.23910


  6 / 282 MEDLINE  
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[PMID]:27638594
[Au] Autor:Carter RL; Wrabetz L; Jalal K; Orsini JJ; Barczykowski AL; Matern D; Langan TJ
[Ad] Endereço:Department of Biostatistics, Population Health Observatory, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York.
[Ti] Título:Can psychosine and galactocerebrosidase activity predict early-infantile Krabbe's disease presymptomatically?
[So] Source:J Neurosci Res;94(11):1084-93, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early-infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various "abnormal groups," including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false-positive rate of existing univariate methods of diagnosis with our new BVNL-based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two-tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two-tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Galactosilceramidase/metabolismo
Leucodistrofia de Células Globoides/diagnóstico
Leucodistrofia de Células Globoides/metabolismo
Triagem Neonatal/métodos
Psicosina/metabolismo
[Mh] Termos MeSH secundário: Feminino
Seres Humanos
Recém-Nascido
Masculino
Valor Preditivo dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
2238-90-6 (Psychosine); 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.23793


  7 / 282 MEDLINE  
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[PMID]:27638589
[Au] Autor:Nogueira-Rodrigues J; Brites P; Sousa MM
[Ad] Endereço:Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
[Ti] Título:Axonal pathology in Krabbe's disease: The cytoskeleton as an emerging therapeutic target.
[So] Source:J Neurosci Res;94(11):1037-41, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In Krabbe's disease (KD), demyelination and myelin-independent axonal and neuronal defects contribute to the severe neuropathology. The toxic substrate that accumulates in this disease, psychosine, induces alterations in membrane lipid rafts with downstream consequences to cellular signaling pathways that include impaired protein kinase C, ERK, and AKT-glycogen synthase kinase-3ß (GSK3ß) activation. In addition to impaired recruitment of signaling proteins to lipid rafts, endocytosis and axonal transport are affected in KD. Defects in AKT-GSK3ß activation, a central pathway regulating microtubule stability, together with alterations in neurofilaments and microtubules and severely defective axonal transport, highlight the importance of the neuronal cytoskeleton in KD. This Review critically discusses these primary neuronal defects as well as new windows for action opened by their identification that may contribute to effectively correct the neuropathology that underlies this disorder. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Axônios/patologia
Citoesqueleto/fisiologia
Leucodistrofia de Células Globoides/patologia
Leucodistrofia de Células Globoides/terapia
Neurônios/patologia
[Mh] Termos MeSH secundário: Axônios/metabolismo
Psicosina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
2238-90-6 (Psychosine)
[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.23771


  8 / 282 MEDLINE  
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[PMID]:27638585
[Au] Autor:Bradbury AM; Bagel JH; Jiang X; Swain GP; Prociuk ML; Fitzgerald CA; O'Donnell PA; Braund KG; Ory DS; Vite CH
[Ad] Endereço:Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. brada@vet.upenn.edu.
[Ti] Título:Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe's disease).
[So] Source:J Neurosci Res;94(11):1007-17, 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 debilitating and always fatal pediatric neurodegenerative disease caused by a mutation in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC). In the absence of GALC, progressive loss of myelin and accumulation of a neurotoxic substrate lead to incapacitating loss of motor and cognitive function and death, typically by 2 years of age. Currently, there is no cure. Recent convincing evidence of the therapeutic potential of combining gene and cell therapies in the murine model of GLD has accelerated the requirement for validated markers of disease to evaluate therapeutic efficacy. Here we demonstrate clinically relevant and quantifiable measures of central (CNS) and peripheral (PNS) nervous system disease progression in the naturally occurring canine model of GLD. As measured by brainstem auditory-evoked response testing, GLD dogs demonstrated a significant increase in I-V interpeak latency and hearing threshold at all time points. Motor nerve conduction velocities (NCVs) in GLD dogs were significantly lower than normal by 12-16 weeks of age, and sensory NCV was significantly lower than normal by 8-12 weeks of age, serving as a sensitive indicator of peripheral nerve dysfunction. Post-mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and the PNS. Additionally, cerebrospinal fluid psychosine concentrations were significantly elevated in GLD dogs, demonstrating potential as a biochemical marker of disease. These data demonstrate that CNS and PNS disease progression can be quantified over time in the canine model of GLD with tools identical to those used to assess human patients. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Potenciais Evocados Auditivos do Tronco Encefálico/genética
Leucodistrofia de Células Globoides/complicações
Leucodistrofia de Células Globoides/genética
Doenças do Sistema Nervoso
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Cães
Estimulação Elétrica
Feminino
Galactosilceramidase/genética
Seres Humanos
Leucodistrofia de Células Globoides/diagnóstico por imagem
Leucodistrofia de Células Globoides/veterinária
Imagem por Ressonância Magnética
Masculino
Mutação de Sentido Incorreto/genética
Sistema Nervoso/diagnóstico por imagem
Sistema Nervoso/patologia
Sistema Nervoso/fisiopatologia
Doenças do Sistema Nervoso/diagnóstico por imagem
Doenças do Sistema Nervoso/etiologia
Doenças do Sistema Nervoso/metabolismo
Doenças do Sistema Nervoso/terapia
Condução Nervosa/genética
Psicosina/líquido cefalorraquidiano
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
2238-90-6 (Psychosine); 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.23838


  9 / 282 MEDLINE  
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[PMID]:27638584
[Au] Autor:Won JS; Singh AK; Singh I
[Ad] Endereço:Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
[Ti] Título:Biochemical, cell biological, pathological, and therapeutic aspects of Krabbe's disease.
[So] Source:J Neurosci Res;94(11):990-1006, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Krabbe's disease (KD; also called globoid cell leukodystrophy) is a genetic disorder involving demyelination of the central (CNS) and peripheral (PNS) nervous systems. The disease may be subdivided into three types, an infantile form, which is the most common and severe; a juvenile form; and a rare adult form. KD is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase activity in lysosomes, leading to accumulation of galactoceramide and neurotoxic galactosylsphingosine (psychosine [PSY]) in macrophages (globoid cells) as well as neural cells, especially in oligodendrocytes and Schwann cells. This ultimately results in damage to myelin in both CNS and PNS with associated morbidity and mortality. Accumulation of PSY, a lysolipid with detergent-like properties, over a threshold level could trigger membrane destabilization, leading to cell lysis. Moreover, subthreshold concentrations of PSY trigger cell signaling pathways that induce oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, endothelial/vascular dysfunctions, and neuronal and axonal damage. From the time the "psychosine hypothesis" was proposed, considerable efforts have been made in search of an effective therapy for lowering PSY load with pharmacological, gene, and stem cell approaches to attenuate PSY-induced neurotoxicity. This Review focuses on the recent advances and prospective research for understanding disease mechanisms and therapeutic approaches for KD. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Leucodistrofia de Células Globoides/patologia
Leucodistrofia de Células Globoides/terapia
[Mh] Termos MeSH secundário: Animais
Encéfalo/patologia
Doenças Desmielinizantes
Galactosilceramidase/deficiência
Seres Humanos
Leucodistrofia de Células Globoides/classificação
Leucodistrofia de Células Globoides/genética
Lisossomos/enzimologia
Sistema Nervoso/patologia
Neurônios/metabolismo
Neurônios/patologia
Psicosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
2238-90-6 (Psychosine); 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.23873


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[PMID]:27638582
[Au] Autor:Spassieva S; Bieberich E
[Ad] Endereço:Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas.
[Ti] Título:Lysosphingolipids and sphingolipidoses: Psychosine in Krabbe's disease.
[So] Source:J Neurosci Res;94(11):974-81, 2016 Nov.
[Is] ISSN:1097-4547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Until recently, lipids were considered inert building blocks of cellular membranes. This changed three decades ago when lipids were found to regulate cell polarity and vesicle transport, and the "lipid raft" concept took shape. The lipid-driven membrane anisotropy in form of "rafts" that associate with proteins led to the view that organized complexes of lipids and proteins regulate various cell functions. Disturbance of this organization can lead to cellular, tissue, and organ malfunction. Sphingolipidoses, lysosomal storage diseases that are caused by enzyme deficiencies in the sphingolipid degradation pathway, were found to be particularly detrimental to the brain. These enzyme deficiencies result in accumulation of sphingolipid metabolites in lysosomes, although it is not yet clear how this accumulation affects the organization of lipids in cellular membranes. Krabbe's disease (KD), or globoid cell leukodystrophy, was one of the first sphingolipidosis for which the raft concept offered a potential mechanism. KD is caused by mutations in the enzyme ß-galactocerebrosidase; however, elevation of its substrate, galactosylceramide, is not observed or considered detrimental. Instead, it was found that a byproduct of galactosylceramide metabolism, the lysosphingolipid psychosine, is accumulated. The "psychosine hypothesis" has been refined by showing that psychosine disrupts lipid rafts and vesicular transport critical for the function of glia and neurons. The role of psychosine in KD is an example of how the disruption of sphingolipid metabolism can lead to elevation of a toxic lysosphingolipid, resulting in disruption of cellular membrane organization and neurotoxicity. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Glicosídeo Hidrolases/genética
Leucodistrofia de Células Globoides/genética
Leucodistrofia de Células Globoides/metabolismo
Mutação/genética
Psicosina/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Encéfalo/patologia
Glicosídeo Hidrolases/deficiência
Seres Humanos
Leucodistrofia de Células Globoides/patologia
Microdomínios da Membrana/genética
Microdomínios da Membrana/metabolismo
Psicosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
2238-90-6 (Psychosine); EC 3.2.1.- (Glycoside Hydrolases); EC 3.2.1.146 (exo-beta-D-galactofuranosidase)
[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.23888



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