Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent

被引:65
作者
Gondré-Lewis, MC [1 ]
McGlynn, R [1 ]
Walkley, SU [1 ]
机构
[1] Albert Einstein Coll Med, Rose F Kennedy Ctr Res Mental Retardat & Human De, Sidney Weisner Lab Genet Neurol Dis, Dept Neurosci, Bronx, NY 10461 USA
关键词
D O I
10.1016/S0960-9822(03)00531-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Niemann-Pick type C (NPC) disease is a lysosomal disorder commonly caused by a recessive mutation in NPC1, which encodes an integral membrane protein with regions of homology to the morphogen receptor, Patched, and to 3-hydroxy-3-methylglutaryl coenzyme A reductase [1, 2]. Neurons in NPC disease exhibit extensive storage of free cholesterol and glycosphin-golipids (GSLs), including GM2 and GM3 gangliosides [3,4,5]. Most studies have viewed cholesterol storage as primary, with NPC1 functioning as a retroendocytic transporter for regulation of cholesterol homeostasis [3, 6, 7, 8]. Here, we analyze the effects of genetically depriving NPC neurons of complex gangliosides by creating mice doubly deficient in both NPC1 and the GSL synthetic enzyme, GM2/GD2 synthase (GaINAcT). Ganglioside and cholesterol expression in neurons of NPC1(-/-)/GaINAcT+/+, NPC1(-/-)/GaINAcT-/-, NPC+/+/GaINAcT-/-, and WT mice was examined in situ by immunocytochemical and histochemical methods. Neurons in double-deficient mice lacked intraneuronal GM2 accumulation as expected, but remarkably also exhibited absence or dramatic reduction in free cholesterol. Neurons storing cholesterol consistently showed GM3 accumulation but some GM3-positive neurons lacked cholesterol storage. These findings provide a compelling argument that cholesterol sequestration in NPC1-deficient neurons is ganglioside dependent and suggest that the function of NPC1 in these cells may be more closely linked to homeostatic control of GSLs than cholesterol.
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页码:1324 / 1329
页数:6
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