Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment.
Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment.
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DOI：
10.1523/jneurosci.1317-11.2011
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发表时间：
2011-06-22
期刊：
影响因子：
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通讯作者：
Dietschy JM
中科院分区：
文献类型：
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作者：
Aqul A;Liu B;Ramirez CM;Pieper AA;Estill SJ;Burns DK;Liu B;Repa JJ;Turley SD;Dietschy JM
虽然未酯化胆固醇(C)对重塑神经元质膜至关重要，但其在某些神经退行性疾病中的作用仍不明确。从细胞周液中摄取甾醇需要涉及两种溶酶体蛋白的加工，溶酶体酸脂肪酶（LAL）水解C酯和NPC1。在全身性组织中，任何一种蛋白的失活都会导致固醇积累和细胞死亡，但在大脑中，仅NPC1的失活会导致C封存和神经退行性变。当注射到npc1-/-小鼠的中枢神经系统时，HP-β- cd，一种已知可以阻止C积累的化合物，在整个大脑中扩散，并在6.5小时的半时间内被排出体外。这种药物会抑制C合成，升高C酯，抑制SREBP2靶基因，激活LXR控制基因。这些发现表明，HP-β-CD促进了被隔离的C从溶酶体向CNS细胞胞浆室中代谢活跃的C池的运动。该药物在脑内的ED50为~ 0.5 mg/kg，治疗效果持续7天以上。在3 ~ 7周龄的npc1-/-动物脑室系统持续输注HP-β- cd，使生化异常恢复正常，并完全防止预期的神经退行性变。这些研究支持神经元不断从间质液中获取C以允许质膜更新和重塑的概念。NPC1的失活导致溶酶体C隔离和神经退行性变，但这可以通过连续直接向中枢神经系统注射HP-β-CD来预防。
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 (LAL) that hydrolyzes C esters and NPC1. 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, 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 SREBP2 target genes, and activation of LXR 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 more than 7 days. 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.