TY - JOUR
T1 - Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport
AU - Sleat, David E.
AU - Wiseman, Jennifer A.
AU - El-Banna, Mukarram
AU - Price, Sandy M.
AU - Verot, Lucie
AU - Shen, Michael M.
AU - Tint, G. Stephen
AU - Vanier, Marie T.
AU - Walkley, Steven U.
AU - Lobel, Peter
PY - 2004/4/20
Y1 - 2004/4/20
N2 - Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by a lysosomal accumulation of cholesterol and other lipids within the cells of patients. Clinically identical forms of NPC disease are caused by defects in either of two different proteins: NPC1, a lysosomal-endosomal transmembrane protein and NPC2, a soluble lysosomal protein with cholesterol binding properties. Although it is clear that NPC1 and NPC2 are required for the egress of lipids from the lysosome, the precise roles of these proteins in this process is unknown. To gain insight into the normal function of NPC2 and to investigate its interactions, if any, with NPC1, we have generated a murine NPC2 hypomorph that expresses 0-4% residual protein in different tissues and have examined its phenotype in the presence and absence of NPC1. The phenotypes of NPC1 and NPC2 single mutants and an NPC1;NPC2 double mutant are similar or identical in terms of disease onset and progression, pathology, neuronal storage, and biochemistry of lipid accumulation. These findings provide genetic evidence that the NPC1 and NPC2 proteins function in concert to facilitate the intracellular transport of lipids from the lysosome to other cellular sites.
AB - Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by a lysosomal accumulation of cholesterol and other lipids within the cells of patients. Clinically identical forms of NPC disease are caused by defects in either of two different proteins: NPC1, a lysosomal-endosomal transmembrane protein and NPC2, a soluble lysosomal protein with cholesterol binding properties. Although it is clear that NPC1 and NPC2 are required for the egress of lipids from the lysosome, the precise roles of these proteins in this process is unknown. To gain insight into the normal function of NPC2 and to investigate its interactions, if any, with NPC1, we have generated a murine NPC2 hypomorph that expresses 0-4% residual protein in different tissues and have examined its phenotype in the presence and absence of NPC1. The phenotypes of NPC1 and NPC2 single mutants and an NPC1;NPC2 double mutant are similar or identical in terms of disease onset and progression, pathology, neuronal storage, and biochemistry of lipid accumulation. These findings provide genetic evidence that the NPC1 and NPC2 proteins function in concert to facilitate the intracellular transport of lipids from the lysosome to other cellular sites.
UR - http://www.scopus.com/inward/record.url?scp=11144355005&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=11144355005&partnerID=8YFLogxK
U2 - 10.1073/pnas.0308456101
DO - 10.1073/pnas.0308456101
M3 - Article
C2 - 15071184
AN - SCOPUS:11144355005
SN - 0027-8424
VL - 101
SP - 5886
EP - 5891
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -