Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet
Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet
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DOI：
10.1038/nm.2833
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发表时间：
2012-07-01
期刊：
影响因子：
82.9
通讯作者：
Nave, Klaus-Armin
中科院分区：
文献类型：
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作者：
Saher, Gesine;Rudolphi, Fabian;Nave, Klaus-Armin
PLP1（蛋白脂蛋白基因1）的重复和随后髓磷脂蛋白PLP（也称为DM20）在少突胶质细胞中的过度表达是导致Pelizaeus-Merzbacher病（PMD）的最常见原因，PMD是一种致命的白质营养不良(1)，没有治疗选择（2,3）。PLP与胆固醇结合，并包含在膜脂筏微域内(4)。胆固醇可用性是中枢神经系统髓磷脂合成的限速因子(5)。带有额外Plp1基因拷贝的转基因小鼠(6)是PMD的精确模型。髓鞘发育异常（6-8），随后脱髓鞘（9,10），继发性炎症和轴突损伤导致这些小鼠出现严重的运动障碍（9,10）。在plp1转基因少突胶质细胞中，PLP和胆固醇在晚期内体和溶酶体（内体/溶酶体）中积累（9,11-13），这促使我们进一步研究胆固醇在PMD中的作用。在这里，我们表明胆固醇本身促进正常的PLP运输和饮食胆固醇影响PMD病理。在一项临床前试验中，给PMD小鼠喂食富含胆固醇的食物。这恢复了少突胶质细胞的数量，改善了细胞内PLP的积累。髓磷脂含量增加，炎症和胶质瘤减少，运动缺陷改善。即使在出现临床症状后，胆固醇治疗也能防止疾病进展。膳食胆固醇不降低Plp1的过表达，但促进了PLP进入髓鞘膜。这些发现可能对PMD患者的治疗干预具有启示意义。
Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy(1) without therapeutic options(2,3). PLP binds cholesterol and is contained within membrane lipid raft microdomains(4). Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis(5). Transgenic mice with extra copies of the Plp1 gene(6) are accurate models of PMD. Dysmyelination(6-8) followed by demyelination(9,10), secondary inflammation and axon damage contribute to the severe motor impairment in these mice(9,10). The finding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes)(9,11-13), prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.