Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease
Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease
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DOI：
10.1093/hmg/dds324
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发表时间：
2012-11-15
影响因子：
3.5
通讯作者：
Lieberman, Andrew P.
中科院分区：
文献类型：
--
作者：
Elrick, Matthew J.;Yu, Ting;Lieberman, Andrew P.
NiemannPickC型疾病(NPC)是一种儿童起病的神经退行性疾病，由NPC1或NPC2基因突变引起的脂质运输缺陷引起。自噬小体的显著聚集是鼻咽癌细胞的一个显著特征，但对自噬中与疾病相关的改变及其在发病机制中的作用尚缺乏详细的了解。先前的研究表明，鼻咽癌疾病中的脂质储存诱导了自噬。在这里，我们还表明，NPC1缺乏症的自噬小体的清除是由于储存的脂类抑制溶酶体的蛋白酶活性而受损的。我们还证明了自噬途径是鼻咽癌溶酶体中储存胆固醇的一个来源，从而创建了一个正反馈循环，在这个循环中，自噬诱导通过增加脂肪储存来加剧疾病。抑制自噬减少了NPC1缺陷细胞中胆固醇的储存并恢复了正常的溶酶体蛋白分解，支持了自噬途径激活促进疾病发病的模型。
NiemannPick type C disease (NPC) is a childhood onset neurodegenerative disorder arising from lipid-trafficking defects caused by mutations in the NPC1 or NPC2 gene. Marked accumulation of autophagosomes is a prominent feature of NPC cells, yet a detailed understanding of the disease-associated alterations in autophagy and their role in pathogenesis has been lacking. Prior studies have shown that lipid storage in NPC disease induces autophagy. Here, we additionally show that the clearance of autophagosomes in NPC1 deficiency is impaired due to inhibition of lysosomal protease activity by stored lipids. We also demonstrate that the autophagic pathway is a source of stored cholesterol in the NPC lysosome, thus creating a positive feedback loop wherein autophagy induction exacerbates the disease via increased lipid storage. Inhibition of autophagy reduces cholesterol storage and restores normal lysosomal proteolysis in NPC1-deficient cells, supporting a model in which activation of the autophagic pathway promotes disease pathogenesis.