自噬
NPC1
生物
尼曼-皮克病,C型
溶酶体
蛋白质水解
发病机制
细胞生物学
溶酶体贮存病
胆固醇
免疫学
内分泌学
生物化学
内体
酶
细胞凋亡
细胞内
作者
Matthew J. Elrick,Ting Yu,Chan Chung,Andrew P. Lieberman
摘要
Niemann -Pick type C disease (NPC) is a childhood onset neurodegenerative disorder arising from lipidtrafficking 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.
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