Abstract
In prior studies, our laboratory showed that psychosine accumulates and disrupts lipid rafts in brain membranes of Krabbe’s disease. A model of lipid raft disruption helped explaining psychosine’s effects on several signaling pathways important for oligodendrocyte survival and differentiation but provided more limited insight in how this sphingolipid caused demyelination. Here, we have studied how this cationic inverted coned lipid affects the fluidity, stability and structure of myelin and plasma membranes. Using a combination of cutting-edge imaging techniques in non-myelinating (red blood cell), and myelinating (oligodendrocyte) cell models, we show that psychosine is sufficient to disrupt sphingomyelin-enriched domains, increases the rigidity of localized areas in the plasma membrane, and promotes the shedding of membranous microvesicles. The same physicochemical and structural changes were measured in myelin membranes purified from the mutant mouse Twitcher, a model for Krabbe’s disease. Areas of higher rigidity were measured in Twitcher myelin and correlated with higher levels of psychosine and of myelin microvesiculation. These results expand our previous analyses and support, for the first time a pathogenic mechanism where psychosine’s toxicity in Krabbe disease involves deregulation of cell signaling not only by disruption of membrane rafts, but also by direct local destabilization and fragmentation of the membrane through microvesiculation. This model of membrane disruption may be fundamental to introduce focal weak points in the myelin sheath, and consequent diffuse demyelination in this leukodystrophy, with possible commonality to other demyelinating disorders.
Highlights
Krabbe’s disease is a genetic leukodystrophy where mutations in the galactosyl-ceramidase gene cause the aberrant accumulation of undigested galactolipids [1]
Psychosine, which is considered to cause the death of oligodendrocytes and demyelination in Krabbe patients, is a sphingolipid that accumulates in lipid rafts originating from the brain, where it modulates associated signaling and endocytosis [3, 26]
By using three different experimental systems including RBCs, oligodendrocytes, and myelin, our results support a model where the insertion of psychosine molecules in concentrations that represent those found in peripheral blood and nervous tissue from sick Twitcher mice, results in architectural and dynamic disorganization and destabilization of the membrane
Summary
Krabbe’s disease is a genetic leukodystrophy where mutations in the galactosyl-ceramidase gene cause the aberrant accumulation of undigested galactolipids [1]. Galactosylsphingosine, known as psychosine, has been notoriously indicated as the main sphingolipid. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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