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 
(beta-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.