scholarly journals Identification of a Molecular Target of Psychosine and Its Role in Globoid Cell Formation

2001 ◽  
Vol 153 (2) ◽  
pp. 429-434 ◽  
Author(s):  
Dong-Soon Im ◽  
Christopher E. Heise ◽  
Tuan Nguyen ◽  
Brian F. O'Dowd ◽  
Kevin R. Lynch
Keyword(s):  
Cell Death ◽  
Cultured Cells ◽  
Cell Formation ◽  
Molecular Target ◽  
Globoid Cell Leukodystrophy ◽  
Multinuclear Cells ◽  
G Protein Coupled ◽  
Degradative Enzyme ◽  
Globoid Cell ◽  
Globoid Cells

Globoid cell leukodystrophy (GLD) is characterized histopathologically by apoptosis of oligodendrocytes, progressive demyelination, and the existence of large, multinuclear (globoid) cells derived from perivascular microglia. The glycosphingolipid, psychosine (d-galactosyl-β-1,1′ sphingosine), accumulates to micromolar levels in GLD patients who lack the degradative enzyme galactosyl ceramidase. Here we document that an orphan G protein–coupled receptor, T cell death–associated gene 8, is a specific psychosine receptor. Treatment of cultured cells expressing this receptor with psychosine or structurally related glycosphingolipids results in the formation of globoid, multinuclear cells. Our discovery of a molecular target for psychosine suggests a mechanism for the globoid cell histology characteristic of GLD, provides a tool with which to explore the disjunction of mitosis and cytokinesis in cell cultures, and provides a platform for developing a medicinal chemistry for psychosine.

scholarly journals Inhibition of Cytokinesis by a Lipid Metabolite, Psychosine

2000 ◽  
Vol 149 (4) ◽  
pp. 943-950 ◽  
Author(s):  
Takayuki Kanazawa ◽  
Sachiko Nakamura ◽  
Michiko Momoi ◽  
Toshiyuki Yamaji ◽  
Hiromu Takematsu ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Neurological Disorder ◽  
Globoid Cell Leukodystrophy ◽  
Cleavage Furrow ◽  
Adherent Cells ◽  
Actin Reorganization ◽  
Multinuclear Cells ◽  
Cellular Components ◽  
Globoid Cell ◽  
Globoid Cells

Although a number of cellular components of cytokinesis have been identified, little is known about the detailed mechanisms underlying this process. Here, we report that the lipid metabolite psychosine (galactosylsphingosine), derived from galactosylceramide, induced formation of multinuclear cells from a variety of nonadherent and adherent cells due to inhibition of cytokinesis. When psychosine was added to the human myelomonocyte cell line U937, which was the most sensitive among the cell lines tested, cleavage furrow formed either incompletely or almost completely. However, abnormal contractile movement was detected in which the cellular contents of one of the hemispheres of the contracting cell were transferred into its counterpart. Finally, the cleavage furrow disappeared and cytokinesis was reversed. Psychosine treatment also induced giant clots of actin filaments in the cells that probably consisted of small vacuoles with filamentous structures, suggesting that psychosine affected actin reorganization. These observations could account for the formation of multinuclear globoid cells in the brains of patients with globoid cell leukodystrophy, a neurological disorder characterized by the accumulation of psychosine due to galactosylceramidase deficiency.

Correction of the Galactocerebrosidase Deficiency in Globoid Cell Leukodystrophy-Cultured Cells by SL3-3 Retroviral-Mediated Gene Transfer

1996 ◽  
Vol 218 (3) ◽  
pp. 766-771 ◽  
Author(s):  
Miguel A. Gama Sosa ◽  
Rita De Gasperi ◽  
Samir Undevia ◽  
Joseph Yeretsian ◽  
Strutha C. Rouse II ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cultured Cells ◽  
Globoid Cell Leukodystrophy ◽  
Globoid Cell

scholarly journals Globoid cell leukodystrophy (Krabbe disease) in a Merino sheep

2018 ◽  
Vol 31 (1) ◽  
pp. 118-121 ◽  
Author(s):  
Effie Lee ◽  
Maria Fuller ◽  
Mandi Carr ◽  
Jim Manavis ◽  
John Finnie
Keyword(s):  
Matched Control ◽  
Brain Lesions ◽  
Krabbe Disease ◽  
Globoid Cell Leukodystrophy ◽  
Clinicopathologic Features ◽  
Neurologic Disorder ◽  
Merino Sheep ◽  
Cerebellar Peduncles ◽  
Globoid Cell ◽  
Globoid Cells

We describe the clinicopathologic features of an ovine case of Krabbe disease (globoid cell leukodystrophy). Brain lesions, sometimes bilaterally distributed, were present in the cerebellar peduncles, cerebellar folia white matter, medulla, pons, and spinal cord and characterized by marked myelin loss and numerous large macrophages (globoid cells), which tended to aggregate perivascularly. Gemistocytic astrocytes were abundant, and their nuclei were frequently abnormal. The activity of the deficient enzyme, galactosylceramide β-galactosidase, was undetectable in this neurologic disorder compared to age- and breed-matched control brains, and levels of the neurotoxic substrate, psychosine, were markedly elevated.

DNA nick end labeling: a reliable marker for apoptosis?

1995 ◽  
Vol 53 ◽  
pp. 962-963
Author(s):  
Anne F. Bushnell ◽  
Sarah Webster ◽  
Lynn S. Perlmutter
Keyword(s):  
Cell Death ◽  
Cultured Cells ◽  
Apoptotic Cell ◽  
Morphological Characteristics ◽  
Detection Methods ◽  
Tissue Preparation ◽  
Preparation Methods ◽  
Dna Laddering ◽  
Disease States ◽  
Reliable Marker

Apoptosis, or programmed cell death, is an important mechanism in development and in diverse disease states. The morphological characteristics of apoptosis were first identified using the electron microscope. Since then, DNA laddering on agarose gels was found to correlate well with apoptotic cell death in cultured cells of dissimilar origins. Recently numerous DNA nick end labeling methods have been developed in an attempt to visualize, at the light microscopic level, the apoptotic cells responsible for DNA laddering.The present studies were designed to compare various tissue processing techniques and staining methods to assess the occurrence of apoptosis in post mortem tissue from Alzheimer's diseased (AD) and control human brains by DNA nick end labeling methods. Three tissue preparation methods and two commercial DNA nick end labeling kits were evaluated: the Apoptag kit from Oncor and the Biotin-21 dUTP 3' end labeling kit from Clontech. The detection methods of the two kits differed in that the Oncor kit used digoxigenin dUTP and anti-digoxigenin-peroxidase and the Clontech used biotinylated dUTP and avidinperoxidase. Both used 3-3' diaminobenzidine (DAB) for final color development.

scholarly journals Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

Glia ◽  
2021 ◽  
Author(s):  
M. Laura Feltri ◽  
Nadav I. Weinstock ◽  
Jacob Favret ◽  
Narayan Dhimal ◽  
Lawrence Wrabetz ◽  
...  
Keyword(s):  
Globoid Cell Leukodystrophy ◽  
Globoid Cell

scholarly journals Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

2021 ◽  
Author(s):  
Elisabeth Mangiameli ◽  
Anna Cecchele ◽  
Francesco Morena ◽  
Francesca Sanvito ◽  
Vittoria Matafora ◽  
...  
Keyword(s):  
Globoid Cell Leukodystrophy ◽  
Cell Type ◽  
Disease Phenotypes ◽  
Specific Disease ◽  
Cell Type Specific ◽  
Human Ipsc ◽  
Globoid Cell

TAMI-62. METHIONINE METABOLISM CLOSELY RELATED WITH SELF-RENEW, PLURIPOTENCY AND CELL DEATH IN GICS THROUGH MODIFICATION OF CHOLESTEROL BIOSYNTHESIS, RIBOSOMAL RNA AND AUTOPHAGY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi211-vi211
Author(s):  
Kiyotaka Yokogami ◽  
Hideo Takeshima
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Ribosomal Rna ◽  
Cell Activation ◽  
Cultured Cells ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Dna Demethylation ◽  
Methionine Metabolism ◽  
Starting Point

Abstract Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 and FOXM1, (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation and (vi) possible connection between methionine metabolism and pluripotency, protein synthesis through cholesterol metabolism: SREBF2-FOXM1 and ACA43 axis, respectively. (vii) Disruption of autophagy by insufficient formation of macroautophagosomes. In conclusion, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis, ribosomal RNA and autophagy.

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