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Psychosine, cytokinesis, and orphan receptors. Unexpected connections.

Mitchison TJ - J. Cell Biol. (2001)

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

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Completing the connection, Im et al. 2001 showed that the U937 cells shown by Kanazawa et al. 2000 to become multinucleate in response to psychosine express TDAG8 endogenously, whereas other cell lines that do not respond do not express this receptor... Im et al. 2001 concluded that TDAG8 is the receptor for psychosine and a cytokinesis blocker... Before exploring the implications, it is worth critiquing this interesting conclusion... The relatively low apparent affinity of psychosine for TDAG8 is consistent with TDAG8 being the psychosine receptor in GLD, where the psychosine accumulates to high concentrations... But it argues caution in concluding that psychosine is the normal physiological ligand for TDAG8... An endogenous GPCR receptor for a different lysosphingolipid, sphingosylphosphorylcholine, is expressed in the RH7777 cells used by Im et al. 2001 for TDAG8 expression (Im et al. 2000)... Stimulation of these cells with sphingosylphosphorylcholine caused a decrease in [cAMP] comparable to the psychosine/TDAG8 effect, but no induction of multinucleated cells... The much stronger phagocytic activity of phorbol ester differentiated U937 was not affected by psychosine... However, it is not clear whether the differentiated U937 cells still express TDAG8, so the implications are inconclusive... For example, the signaling pathways triggered by psychosine/TDAG8 might interfere with those required for coordinated contraction and membrane insertion during cytokinesis... More work is required to address the mechanism by which psychosine/TDAG8 affects cytokinesis, and perhaps other cortical processes, and to determine if this pathway plays a role in physiological formation of multinucleate cells... The connection that has now been established between psychosine, TDAG8, and cytokinesis has already opened new lines of investigation in these previously unlinked areas.

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Structures of lipids.
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Figure 1: Structures of lipids.

Mentions: Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a severe, inherited, metabolic disorder in which normal myelin formation is blocked, and multinucleate “globoid cells” accumulate in the brain. The primary defect is an absence of the lipid-degrading enzyme galactoceramidase, which cleaves the galactose headgroup from galactoceramide (Fig. 1). Galactoceramidase-deficient mice and dogs provide models for human GLD (Suzuki 1998). Unlike some other lipidoses, the primary substrate of the missing enzyme, galactoceramide, does not accumulate. Instead, a related lipid metabolite, psychosine (Fig. 1), accumulates in the brain (Svennerholm et al. 1980). Suzuki 1998 hypothesized that psychosine is normally broken down by galactoceramidase, and that in its absence psychosine accumulates, causing death of oligodendrocytes. These are the cells that normally synthesize galactoceramide during myelination, so their death would account for the absence of galactoceramide buildup, and also GLD pathology. This “psychosine hypothesis” has stood the test of time, though the mechanism by which psychosine might mediate toxic effects was unknown. The multinucleate globoid cells in GLD are thought to derive from microglia and macrophages (Kanazawa et al. 2000), but the reason they accumulate was unknown.


Psychosine, cytokinesis, and orphan receptors. Unexpected connections.

Mitchison TJ - J. Cell Biol. (2001)

Structures of lipids.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169451&req=5

Figure 1: Structures of lipids.
Mentions: Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a severe, inherited, metabolic disorder in which normal myelin formation is blocked, and multinucleate “globoid cells” accumulate in the brain. The primary defect is an absence of the lipid-degrading enzyme galactoceramidase, which cleaves the galactose headgroup from galactoceramide (Fig. 1). Galactoceramidase-deficient mice and dogs provide models for human GLD (Suzuki 1998). Unlike some other lipidoses, the primary substrate of the missing enzyme, galactoceramide, does not accumulate. Instead, a related lipid metabolite, psychosine (Fig. 1), accumulates in the brain (Svennerholm et al. 1980). Suzuki 1998 hypothesized that psychosine is normally broken down by galactoceramidase, and that in its absence psychosine accumulates, causing death of oligodendrocytes. These are the cells that normally synthesize galactoceramide during myelination, so their death would account for the absence of galactoceramide buildup, and also GLD pathology. This “psychosine hypothesis” has stood the test of time, though the mechanism by which psychosine might mediate toxic effects was unknown. The multinucleate globoid cells in GLD are thought to derive from microglia and macrophages (Kanazawa et al. 2000), but the reason they accumulate was unknown.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Completing the connection, Im et al. 2001 showed that the U937 cells shown by Kanazawa et al. 2000 to become multinucleate in response to psychosine express TDAG8 endogenously, whereas other cell lines that do not respond do not express this receptor... Im et al. 2001 concluded that TDAG8 is the receptor for psychosine and a cytokinesis blocker... Before exploring the implications, it is worth critiquing this interesting conclusion... The relatively low apparent affinity of psychosine for TDAG8 is consistent with TDAG8 being the psychosine receptor in GLD, where the psychosine accumulates to high concentrations... But it argues caution in concluding that psychosine is the normal physiological ligand for TDAG8... An endogenous GPCR receptor for a different lysosphingolipid, sphingosylphosphorylcholine, is expressed in the RH7777 cells used by Im et al. 2001 for TDAG8 expression (Im et al. 2000)... Stimulation of these cells with sphingosylphosphorylcholine caused a decrease in [cAMP] comparable to the psychosine/TDAG8 effect, but no induction of multinucleated cells... The much stronger phagocytic activity of phorbol ester differentiated U937 was not affected by psychosine... However, it is not clear whether the differentiated U937 cells still express TDAG8, so the implications are inconclusive... For example, the signaling pathways triggered by psychosine/TDAG8 might interfere with those required for coordinated contraction and membrane insertion during cytokinesis... More work is required to address the mechanism by which psychosine/TDAG8 affects cytokinesis, and perhaps other cortical processes, and to determine if this pathway plays a role in physiological formation of multinucleate cells... The connection that has now been established between psychosine, TDAG8, and cytokinesis has already opened new lines of investigation in these previously unlinked areas.

Show MeSH