Glial contribution to cyclodextrin-mediated reversal of cholesterol accumulation in murine NPC1-deficient neuronsin vivo

Niemann-Pick type C (NPC) 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 on 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. We find that CD enters the endosomal-lysosomal system of neurons and enables the release of lipid-laden lamellar inclusions, which are then removed from the extracellular space by specific types of glial cells. Thus, CD triggers a concerted action of neurons and glial cells to restore lipid homeostasis in the central nervous system.