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

Abstract

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 (␤-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.

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…Indeed, disrupted calcium homeostasis was found in isolated brain microsomes from a Gaucher disease type 2 patient, the Sandhoff disease mouse ( 285,290 ), and the ASM knockout mouse ( 291 ). Thus, selected abnormal GSL levels could alter LTP by disruption of calcium-mediated vesicular release of neurotransmitters or related receptor functions, as suggested recently for galactosylsphingosine interference of lipid raft assembly ( 283 ). The alteration of LTP in selected GSL disorders also could result from secondary pathology, such as proinfl ammation and neurotrophin defect ( 292,293 ).…”

“…Importantly, this was the fi rst disease in which a lysoglycolipid was implicated as a major pathogen and led to the postulation that lysoglycolipids were the toxic agents that were responsible for the disease progression in many GSL storage diseases. In the twitcher mouse brain, galactosylsphingosine accumulation leads to alteration in lipid raft structure, which may cause abnormal cellular function in oligodendrocyte and Schwann cells and lead to retrograde axonal degeneration ( 283 ). A similar mechanism may be operative in neuronopathic Gaucher disease mice exhibiting increased CNS glucosylsphingosine levels ( 205,208 ).…”

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…A direct pathological role for GalSph has been proposed for the neuropathology of Krabbe disease. GalSph triggers apoptosis of oligodendrocytes and Schwann cells by disrupting lipid rafts in myelinating glia [47,48]. This results in demyelination affecting both the central and peripheral nervous systems [49,50].…”

Human tRNASecassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

“…It is concentrated in membrane rafts, where it is phosphorylated by sphingosine kinase (Hengst et al 2009). Galactosyl-sphingosine (psychosine) also accumulates in membrane rafts and alters their architecture (White et al 2009). In most cell types, 3 sphingosine is present in concentrations that are an order of magnitude lower than that of ceramide which in turn is an order of magnitude lower than sphingomyelin (Hannun and Obeid 2008).…”