Glial contribution to cyclodextrin-mediated reversal of cholesterol accumulation in murine NPC1-deficient neurons in vivo.
Fiche publication
Date publication
août 2021
Journal
Neurobiology of disease
Auteurs
Membres identifiés du Cancéropôle Est :
Mme DEMAIS Valérie, Dr PFRIEGER Frank
Tous les auteurs :
Barthelemy A, Demais V, Stancu IC, Vasile E, Houben T, Reber M, Pallottini V, Perraut M, Reibel S, Pfrieger FW
Lien Pubmed
Résumé
Niemann-Pick type C disease is a rare and fatal lysosomal storage disorder presenting severe neurovisceral symptoms. Disease-causing mutations in genes encoding either NPC1 or NPC2 protein provoke accumulation of cholesterol and other lipids in specific structures of the endosomal-lysosomal system and degeneration of specific cells, notably neurons in the central nervous system (CNS). 2-hydroxypropyl-beta-cyclodextrin (CD) emerged as potential therapeutic approach based on animal studies and clinical data, but the mechanism of action in neurons has remained unclear. To address this topic in vivo, we took advantage of the retina as highly accessible part of the CNS and intravitreal injections as mode of drug administration. Coupling CD to gold nanoparticles allowed us to trace its intracellular location. We report that CD enters the endosomal-lysosomal system of neurons in vivo and enables the release of lipid-laden lamellar inclusions, which are then removed from the extracellular space by specific types of glial cells. Our data suggest that CD induces a concerted action of neurons and glial cells to restore lipid homeostasis in the central nervous system.
Mots clés
Amacrine cells, Astrocytes, Cyclodextrin, Ganglion cells, Inherited metabolic disease, Intravitreal, Lysosome, Microglia, Müller cells, Neutrophil granulocytes
Référence
Neurobiol Dis. 2021 Aug 5;:105469