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Cholesterol Overload Promotes Morphogenesis of a Niemann-Pick C (NPC)-like Compartment Independent of Inhibition of NPC1 or HE1/NPC2 Function

Authors: A, Frolov; K, Srivastava; D, Daphna-Iken; L M, Traub; J E, Schaffer; D S, Ory;

Cholesterol Overload Promotes Morphogenesis of a Niemann-Pick C (NPC)-like Compartment Independent of Inhibition of NPC1 or HE1/NPC2 Function

Abstract

Cholesterol accumulation in an aberrant endosomal/lysosomal compartment is the hallmark of Niemann-Pick type C (NPC) disease. To gain insight into the etiology of the NPC compartment, we studied a novel Chinese hamster ovary cell mutant that was identified through a genetic screen and phenocopies the NPC1 mutation. We show that the M87 mutant harbors a mutation in a gene distinct from the NPC1 and HE1/NPC2 disease genes. M87 cells have increased total cellular cholesterol with accumulation in an aberrant compartment that contains LAMP-1, LAMP-2, and NPC1, but not CI-MPR, similar to the cholesterol-rich compartment in NPC mutant cells. We demonstrate that low-density lipoprotein receptor activity is increased 3-fold in the M87 mutant, and likely contributes to accumulation of excess cholesterol. In contrast to NPC1-null cells, the M87 mutant exhibits normal rates of delivery of endosomal cholesterol to the endoplasmic reticulum and to the plasma membrane. The preserved late endosomal function in the M87 mutant is associated with the presence of NPC1-containing multivesicular late endosomes and supports a role for these multivesicular late endosomes in the sorting and distribution of cholesterol. Our findings implicate cholesterol overload in the formation of an NPC-like compartment that is independent of inhibition of NPC1 or HE1/NPC2 function.

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Keywords

Niemann-Pick Diseases, Membrane Glycoproteins, Base Sequence, Intracellular Signaling Peptides and Proteins, Vesicular Transport Proteins, CHO Cells, Cell Compartmentation, Cholesterol, Receptors, LDL, Niemann-Pick C1 Protein, Amphotericin B, Cricetinae, Morphogenesis, Animals, Cholesterol Esters, Carrier Proteins, DNA Primers, Glycoproteins

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    popularity
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    Top 10%
    influence
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    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
47
Top 10%
Top 10%
Top 10%
gold