TY - JOUR
T1 - Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent
AU - Gondré-Lewis, Marjorie C.
AU - McGlynn, Robert
AU - Walkley, Steven U.
N1 - Funding Information:
We thank Drs. Ronald Schnaar and Richard Proia for providing the GalNAcT knockout mice and Dr. Peter Pentchev for the NPC1 mice. This study was supported by the Ara Parseghian Medical Research Foundation (S.U.W.) and the UNCF/Merck Dissertation Research Fellowship (M.C.G.-L.).
PY - 2003/8/5
Y1 - 2003/8/5
N2 - 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 glycosphingolipids (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 (GalNAcT). Ganglioside and cholesterol expression in neurons of NPC1-/-/GalNAcT+/+, NPC1-/-/GalNAcT-/-, NPC1+/+/GalNAcT-/-, 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.
AB - 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 glycosphingolipids (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 (GalNAcT). Ganglioside and cholesterol expression in neurons of NPC1-/-/GalNAcT+/+, NPC1-/-/GalNAcT-/-, NPC1+/+/GalNAcT-/-, 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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U2 - 10.1016/S0960-9822(03)00531-1
DO - 10.1016/S0960-9822(03)00531-1
M3 - Article
C2 - 12906793
AN - SCOPUS:0041700117
SN - 0960-9822
VL - 13
SP - 1324
EP - 1329
JO - Current Biology
JF - Current Biology
IS - 15
ER -