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The Journal of Neuroscience, May 13, 2009, 29(19):6068-6077; doi:10.1523/JNEUROSCI.5597-08.2009

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Neurobiology of Disease
Psychosine Accumulates in Membrane Microdomains in the Brain of Krabbe Patients, Disrupting the Raft Architecture

Adam B. White,¹ Maria I. Givogri,¹ Aurora Lopez-Rosas,¹ Hongmei Cao,² Richard van Breemen,² Gopal Thinakaran,³ and Ernesto R. Bongarzone¹

Departments of ¹Anatomy and Cell Biology, College of Medicine and ²Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, and ³Department of Neurobiology, University of Chicago, Chicago, Illinois 60637

Correspondence should be addressed to Dr. Ernesto R. Bongarzone, Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, 808 S. Wood Street M/C 512, Chicago, IL 60612. Email: ebongarz{at}uic.edu

Lipid rafts (LRs) are membrane realms characterized by high concentrations of cholesterol and sphingolipids. Often, they are portrayed as scaffolds on which many different signaling molecules can assemble their cascades. The idea of rafts as scaffolds is garnering significant attention as the consequences of LR disruption have been shown to be manifest in multiple signaling pathways. In this study, LRs in the brain of the twitcher (TWI) mouse, a bona-fide model for infant variants of human globoid cell leukodystrophy or Krabbe disease, were investigated. This mouse has deficient activity of GALC (β-galactosylceramidase) that leads to a progressive accumulation of some galactosyl-sphingolipids in the brain. We hypothesized that the accumulation of psychosine (galactosyl-sphingosine) in the TWI CNS may result in the disruption of rafts in different cell populations such as neurons and oligodendrocytes, both cellular targets during disease. In this communication, we demonstrate that psychosine specifically accumulates in LRs in the TWI brain and sciatic nerve and in samples from brains of human Krabbe patients. It is also shown that this accumulation is accompanied by an increase in cholesterol in these domains and changes in the distribution of the LR markers flotillin-2 and caveolin-1. Finally, we show evidence that this phenomenon may provide a mechanism by which psychosine can exert its known inhibitory effect on protein kinase C. This study provides a previously undescribed biophysical aspect for the mechanism of pathogenesis in Krabbe disease.

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Received Nov. 23, 2008; revised April 2, 2009; accepted April 8, 2009.

Correspondence should be addressed to Dr. Ernesto R. Bongarzone, Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, 808 S. Wood Street M/C 512, Chicago, IL 60612. Email: ebongarz{at}uic.edu

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