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

Amélie Barthelemy, Valérie Demais, Izabela Cristina Stancu, Eugeniu Vasile, Tom Houben, Michael Reber, Valentina Pallottini, Martine Perraut, Sophie Reibel, Frank W. Pfrieger

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number105469
JournalNeurobiology of Disease
Volume158
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Amacrine cells
  • Astrocytes
  • Cyclodextrin
  • Ganglion cells
  • Inherited metabolic disease
  • Intravitreal
  • Lysosome
  • Microglia
  • Müller cells
  • Neutrophil granulocytes

ASJC Scopus subject areas

  • Neurology

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