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J Biol Chem, Vol. 275, Issue 6, 4013-4021, February 11, 2000
From the Department of Biochemistry, Dartmouth Medical School,
Hanover, New Hampshire 03755
Niemann-Pick type C (NPC) is a disease that
affects intracellular cholesterol-trafficking pathways. By cloning the
hamster ortholog of NPC1, we identified the molecular
lesions in two independently isolated Chinese hamster ovary cell
mutants, CT60 and CT43. Both mutants lead to premature translational
terminations of the NPC1 protein. Transfecting hamster NPC1
cDNA complemented the defects of the mutants. Investigation of the
CT mutants, their parental cells, and an NPC1-stable transfectant allow
us to present evidence that NPC1 is involved in a post-plasma membrane
cholesterol-trafficking pathway. We found that the initial movement of
low density lipoprotein (LDL)-derived cholesterol to the plasma
membrane (PM) did not require NPC1. After reaching the PM and
subsequent internalization, however, cholesterol trafficking back to
the PM did involve NPC1. Both LDL-derived cholesterol and cholesterol
originating from the PM accumulated in a dense, intracellular
compartment in the CT mutants. Cholesterol movement from this
compartment to the PM or endoplasmic reticulum was defective in the CT
mutants. Our results functionally distinguish the dense, intracellular
compartment from the early endocytic hydrolytic organelle and imply
that NPC1 is involved in sorting cholesterol from the intracellular
compartment back to the PM or to the endoplasmic reticulum.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF182744.
To whom correspondence should be addressed. Tel.: 603-650-1622;
Fax: 603-650-1128; E-mail: Ta.Yuan.Chang@Dartmouth.edu.
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J. C. Cruz and T.-Y. Chang Fate of Endogenously Synthesized Cholesterol in Niemann-Pick Type C1 Cells J. Biol. Chem., December 22, 2000; 275(52): 41309 - 41316. [Abstract] [Full Text] [PDF]
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T. Yamazaki, T.-Y. Chang, C. Haass, and Y. Ihara Accumulation and Aggregation of Amyloid beta -Protein in Late Endosomes of Niemann-Pick Type C Cells J. Biol. Chem., February 2, 2001; 276(6): 4454 - 4460. [Abstract] [Full Text] [PDF]
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N. Sawamura, J.-S. Gong, W. S. Garver, R. A. Heidenreich, H. Ninomiya, K. Ohno, K. Yanagisawa, and M. Michikawa Site-specific Phosphorylation of Tau Accompanied by Activation of Mitogen-activated Protein Kinase (MAPK) in Brains of Niemann-Pick Type C Mice J. Biol. Chem., March 23, 2001; 276(13): 10314 - 10319. [Abstract] [Full Text] [PDF]
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A. R. Leventhal, W. Chen, A. R. Tall, and I. Tabas Acid Sphingomyelinase-deficient Macrophages Have Defective Cholesterol Trafficking and Efflux J. Biol. Chem., November 21, 2001; 276(48): 44976 - 44983. [Abstract] [Full Text] [PDF]
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