Cory R Reiter, Rima Rebiai, Angelika Kwak, Jeff Marshall, Dylan Wozniak, Giusepe Scesa, Duc Nguyen, Emily Rue, Chandimal Pathmasiri, Robert Pijewski, Richard van Breemen, Stephanie Cologna, Stephen J Crocker, M Irene Givogri, Ernesto R Bongarzone
Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with increased disease severity...
January 2022: ASN Neuro