Unesterified Cholesterol Accumulation in Late Endosomes/Lysosomes Causes Neurodegeneration and Is Prevented by Driving Cholesterol Export from This Compartment
- 22 June 2011
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 31 (25), 9404-9413
- https://doi.org/10.1523/jneurosci.1317-11.2011
Abstract
While unesterified cholesterol (C) is essential for remodeling neuronal plasma membranes, its role in certain neurodegenerative disorders remains poorly defined. Uptake of sterol from pericellular fluid requires processing that involves two lysosomal proteins, lysosomal acid lipase, which hydrolyzes C esters, and NPC1 (Niemann-Pick type C1). In systemic tissues, inactivation of either protein led to sterol accumulation and cell death, but in the brain, inactivation of only NPC1 caused C sequestration and neurodegeneration. When injected into the CNS of the npc1−/− mouse, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a compound known to prevent this C accumulation, diffused throughout the brain and was excreted with a t½ of 6.5 h. This agent caused suppression of C synthesis, elevation of C esters, suppression of sterol regulatory-binding protein 2 (SREBP2) target genes, and activation of liver X receptor-controlled genes. These findings indicated that HP-β-CD promoted movement of the sequestered C from lysosomes to the metabolically active pool of C in the cytosolic compartment of cells in the CNS. The ED50 for this agent in the brain was ∼0.5 mg/kg, and the therapeutic effect lasted >7 d. Continuous infusion of HP-β-CD into the ventricular system of npc1−/− animals between 3 and 7 weeks of age normalized the biochemical abnormalities and completely prevented the expected neurodegeneration. These studies support the concept that neurons continuously acquire C from interstitial fluid to permit plasma membrane turnover and remodeling. Inactivation of NPC1 leads to lysosomal C sequestration and neurodegeneration, but this is prevented by the continuous, direct administration of HP-β-CD into the CNS.This publication has 41 references indexed in Scilit:
- Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acidJournal of Lipid Research, 2010
- Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease ProgressionPLOS ONE, 2009
- Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 −/− mouseProceedings of the National Academy of Sciences of the United States of America, 2009
- Central nervous system: cholesterol turnover, brain development and neurodegenerationBiological Chemistry, 2009
- Lysobisphosphatidic Acid Controls Endosomal Cholesterol LevelsOnline Journal of Public Health Informatics, 2008
- Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C diseaseJournal of Lipid Research, 2007
- Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animalJournal of Lipid Research, 2004
- Cholesterol Accumulation in NPC1-Deficient Neurons Is Ganglioside DependentCurrent Biology, 2003
- Cholesterol homeostasis and function in neurons of the central nervous systemCellular and Molecular Life Sciences, 2003
- Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humansJournal of Lipid Research, 1993