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J. Biol. Chem., Vol. 278, Issue 6, 4168-4175, February 7, 2003
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From the Niemann Pick type C (NPC) disease is a
progressive neurodegenerative disorder. In cells lacking functional
NPC1 protein, endocytosed cholesterol accumulates in late
endosomes/lysosomes. We utilized primary neuronal cultures in which
cell bodies and distal axons reside in separate compartments to
investigate the requirement of NPC1 protein for transport of
cholesterol from cell bodies to distal axons. We have recently observed
that in NPC1-deficient neurons compared with wild-type neurons,
cholesterol accumulates in cell bodies but is reduced in distal axons
(Karten, B., Vance, D. E., Campenot, R. B., and Vance,
J. E. (2002) J. Neurochem. 83, 1154-1163). We
now show that NPC1 protein is expressed in both cell bodies and distal
axons. In NPC1-deficient neurons, cholesterol delivered to cell bodies
from low density lipoproteins (LDLs), high density lipoproteins, or
cyclodextrin complexes was transported into axons in normal amounts,
whereas transport of endogenously synthesized cholesterol was impaired.
Inhibition of cholesterol synthesis with pravastatin in wild-type and
NPC1-deficient neurons reduced axonal growth. However, LDLs restored a
normal rate of growth to wild-type but not NPC1-deficient neurons
treated with pravastatin. Thus, although LDL cholesterol is transported into axons of NPC1-deficient neurons, this source of cholesterol does
not sustain normal axonal growth. Over the lifespan of NPC1-deficient neurons, these defects in cholesterol transport might be responsible for the observed altered distribution of cholesterol between cell bodies and axons and, consequently, might contribute to the
neurological dysfunction in NPC disease.
Trafficking of Cholesterol from Cell Bodies to Distal Axons in
Niemann Pick C1-deficient Neurons*
§¶,
**,§¶¶
Canadian Institutes of Health Research Group
on the Molecular and Cell Biology of Lipids and the Departments of
§ Medicine, Biochemistry, and
§§ Cell Biology, University of Alberta,
Edmonton, Alberta T6G 2S2, Canada
*
This work was supported by grants from the Canadian
Institutes for Health Research and the Ara Parseghian Medical Research Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Holder of the Canada Research Chair in Molecular and Cell
Biology of Lipids.
¶¶
To whom correspondence should be addressed: 332 Heritage Medical Research Centre, University of Alberta, Edmonton, AB
T6G 2S2, Canada. Tel.: 780-492-7250; Fax: 780-492-3383; E-mail:
jean.vance@ualberta.ca.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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