Unesterified Cholesterol Accumulation in Late Endosomes/Lysosomes Causes Neurodegeneration and Is Prevented by Driving Cholesterol Export from This Compartment

被引:126
作者
Aqul, Amal [2 ]
Liu, Benny [1 ]
Ramirez, Charina M. [2 ]
Pieper, Andrew A. [3 ,4 ]
Estill, Sandi Jo [4 ]
Burns, Dennis K. [5 ]
Liu, Bing [6 ]
Repa, Joyce J. [1 ,6 ]
Turley, Stephen D. [1 ]
Dietschy, John M. [1 ]
机构
[1] Univ Texas SW Med Sch, Dept Internal Med, Dallas, TX 75390 USA
[2] Univ Texas SW Med Sch, Dept Pediat, Dallas, TX 75390 USA
[3] Univ Texas SW Med Sch, Dept Psychiat, Dallas, TX 75390 USA
[4] Univ Texas SW Med Sch, Dept Biochem, Dallas, TX 75390 USA
[5] Univ Texas SW Med Sch, Dept Pathol, Dallas, TX 75390 USA
[6] Univ Texas SW Med Sch, Dept Physiol, Dallas, TX 75390 USA
关键词
CENTRAL-NERVOUS-SYSTEM; RETROGRADE TRANSPORT; EVERY ORGAN; BRAIN; METABOLISM; DISEASE; HOMEOSTASIS; NEURONS; LIVER; LIPOPROTEINS;
D O I
10.1523/JNEUROSCI.1317-11.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-beta-cyclodextrin (HP-beta-CD), a compound known to prevent this C accumulation, diffused throughout the brain and was excreted with a t(1/2) 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-beta-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 similar to 0.5 mg/kg, and the therapeutic effect lasted > 7 d. Continuous infusion of HP-beta-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-beta-CD into the CNS.
引用
收藏
页码:9404 / 9413
页数:10
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