Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment

Amal Aqul, Benny Liu, Charina M. Ramirez, Andrew A. Pieper, Sandi Jo Estill, Dennis K. Burns, Bing Liu, Joyce J. Repa, Stephen D. Turley, John M. Dietschy

Research output: Contribution to journalArticle

90 Citations (Scopus)

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 t1/2 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.

Original languageEnglish (US)
Pages (from-to)9404-9413
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number25
DOIs
StatePublished - Jun 22 2011

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Endosomes
Cyclodextrins
Lysosomes
Sterols
Cholesterol
Brain
Cell Membrane
Sterol Esterase
Neuronal Plasticity
Extracellular Fluid
Therapeutic Uses
Neurodegenerative Diseases
Transcriptional Activation
Carrier Proteins
Cell Death
Neurons
Genes
Proteins
calcium ascorbate

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. / Aqul, Amal; Liu, Benny; Ramirez, Charina M.; Pieper, Andrew A.; Estill, Sandi Jo; Burns, Dennis K.; Liu, Bing; Repa, Joyce J.; Turley, Stephen D.; Dietschy, John M.

In: Journal of Neuroscience, Vol. 31, No. 25, 22.06.2011, p. 9404-9413.

Research output: Contribution to journalArticle

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AU - Estill, Sandi Jo

AU - Burns, Dennis K.

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