کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5939112 | 1573474 | 2007 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1â/â Mouse Brain
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موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
کاردیولوژی و پزشکی قلب و عروق
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چکیده انگلیسی
Niemann-Pick type C (NPC) disease is an autosomal recessive disorder caused by mutations of NPC1 and NPC2 genes. Progressive neurodegeneration that accompanies NPC is fatal, but the underlying mechanisms are still poorly understood. In the present study, we characterized the association of autophagic-lysosomal dysfunction with cholesterol accumulation in Npc1â/â mice during postnatal development. Brain levels of lysosomal cathepsin D were significantly higher in mutant than in wild-type mice. Increases in cathepsin D occurred first in neurons and later in astrocytes and microglia and were both spatially and temporally associated with intracellular cholesterol accumulation and neurodegeneration. Furthermore, levels of ubiquitinated proteins were higher in endosomal/lysosomal fractions of brains from Npc1â/â mice than from wild-type mice. Immunoblotting results showed that levels of LC3-II were significantly higher in brains of mutant than wild-type mice. Combined LC3 immunofluorescence and filipin staining showed that LC3 accumulated within filipin-labeled cholesterol clusters inside Purkinje cells. Electron microscopic examination revealed the existence of autophagic vacuole-like structures and multivesicles in brains from Npc1â/â mice. These results provide strong evidence that cholesterol accumulation-induced changes in autophagy-lysosome function are closely associated with neurodegeneration in NPC.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The American Journal of Pathology - Volume 171, Issue 3, September 2007, Pages 962-975
Journal: The American Journal of Pathology - Volume 171, Issue 3, September 2007, Pages 962-975
نویسندگان
Guanghong Liao, Yueqin Yao, Jihua Liu, Zhang Yu, Simon Cheung, Ang Xie, Xiaoli Liang, Xiaoning Bi,