Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s disease

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.

Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?

“…For instance, using RBCs and oligodendrocytes, they showed that psychosine disrupts SM-enriched domains and increases the rigidity of local PM areas while promoting the shedding of MVs. Areas of higher rigidity have been confirmed in Twitcher myelin and correlate with higher contents in psychosine and myelin microvesiculation [ 180 ] (see also Section 5.3.5 ).…”

“…For example, in Krabbe disease, the abnormal accumulation of psychosine in the oligodendrocyte membrane disrupts lipid rafts [ 179 ]. This leads to the disruption of several signaling pathways but also to an increased rigidity of localized areas promoting the shedding of MVs [ 180 ], thought to be essential in the demyelination observed in this disease (see also Section 5.1 ).…”

Exosomes: Revisiting their role as “garbage bags”

“…Although caused by mutations in either of the genes of NPC1 or NPC2 proteins involved in cholesterol transport out of lysosomes, Niemann‐Pick type C disease also leads to sphingolipids accumulation in late endosomes/lysosomes. Toxic sphingolipids such as sulfatides or psychosine have been shown to accumulate in some sphingolipidoses and to be secreted with EVs . The cellular ceramide content has also been shown to be regulated by exosome secretion through adiponectin binding to T‐cadherin .…”

“…Toxic sphingolipids such as sulfatides or psychosine have been shown to accumulate in some sphingolipidoses and to be secreted with EVs. 118,119 The cellular ceramide content has also been shown to be regulated by exosome secretion through adiponectin binding to Tcadherin. 120 Adiponectin is a protein secreted by adipocytes as oligomers that bind to T-cadherin, a unique GPI-anchored form of cadherin notably present in lipid rafts of endothelial vascular cells.…”

Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles

“…A recent study revealed a role for the GSL, galactosyl-Sph, and its metabolic enzyme, galactosyl-CDase, in the control of plasma membrane structure and EV shedding. D'Auria et al (98) highlighted the involvement of galactosyl-Sph in alteration of membrane organization and microvesiculation from oligodendrocytes, the glial cell type that deposits myelin along neuronal axons in the central nervous system.…”