Psychosine, Cytokinesis, and Orphan Receptors

One of the most exciting aspects of modern cell biology is the potential to make connections between disparate areas of research, and thus open up new lines of enquiry. Two recent papers have done just this (Kanazawa et al., 2000; Im et al., 2001, this issue). Building on the biochemical defect in an inherited metabolic disease (Suzuki, 1998), these papers reveal an unexpected connection between lipid mediators , G protein–coupled receptor (GPCR) 1 signaling, and cytokinesis mechanism. 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 galactoce-ramidase, which cleaves the galactose headgroup from ga-lactoceramide (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 psy-chosine accumulates, causing death of oligodendrocytes. These are the cells that normally synthesize galactocer-amide 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. To test the hypothesis that accumulated psychosine might trigger formation of multinucleate globoid cells, Kanazawa et al. (2000) treated several cell lines with psy-chosine at concentrations relevant to GLD. They found that a premonocyte-like cell line, U937, responded by becoming multinucleate over a few days. Cytochemistry and time-lapse imaging of dividing cells showed that psycho-sine did not induce cell fusion; rather, it blocked cytokine-sis, uncoupling mitosis from cell division. This discovery is the first reported inhibition of cytokinesis by a physiologically occurring small molecule, and a large step forward in understanding the pathogenesis of GLD. However, it was not clear how the target of psychosine might be discovered. Psychosine is a lysolipid, with detergent-like properties , so its target might in principle be some aspect of membrane biophysics rather than a specific protein. While hunting …