Exosomal Mobilization of the Neurotoxin Psychosine: A Contributing Pathogenic Mechanism in Krabbe Disease

BONGARZONE, ERNESTO R; D'AURIA, LUDOVIC; PITUCH, KATARZYNA; MOYANO, ANA LIS; GIVOGRI, MARIA I

Simposio; 45th Annual ASN Meeting; 2014

A growing body of evidence shows that certain sphingolipids may elicit pathogenic pathways under non-physiological conditions. Galactosyl-sphingosine (psychosine) is a sphingolipid that accumulates to toxic levels in Krabbe disease. Psychosine is known to activate degenerative mechanisms in oligodendrocytes and neurons, but the steps involved in these effects are not completely clear. Our studies found that psychosine accumulates preferentially in plasma membrane lipid rafts. Lipid rafts are membrane domains characterized by high concentrations of cholesterol and sphingolipids, acting as scaffolds upon which many different signaling molecules can assemble their cascades. In recent years, rafts have also been associated with the generation of exosomes, which are microvesicles released via the formation of multivesicular bodies. Of interest, exosomes have been portrayed as means to transfer information from cell to cell and for regulation of signaling pathways. The possibility that sphingolipids with toxic properties segregate into these secretory vesicles has not been addressed in detail. We hypothesized that psychosine accumulates in exosomes and is capable of cell-to-cell transfer in the disease brain, activating pathogenic pathways in naïve cells. In this communication, we studied exosomes prepared from neural cells isolated from the brain of thetwitcher mouse, a bona-fide model for infant variants of human Krabbe disease, which accumulates psychosine. We will show evidence demonstrating that psychosine is released from neural cells using the exosomal pathway. We will discuss the relevance of this pathogenic mechanism in this disease and other sphingolipidoses as well as for basic cellular processes such as regulation of neurogliogenesis.This study is funded by NIH (R01 NS065808) and the Legacy for Angels Foundation Awards to ERB.