Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann–Pick C1-deficient neurons

Authors

  • Barbara Karten,

    1. Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Departments of
    2. Medicine,
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    • 1

      Supported by postdoctoral fellowships from the Alberta Heritage Foundation for Medical Research and the Deutsche Forschungsgemeinschaft (Forschungsstipendium KA1578/1).

  • Dennis E. Vance,

    1. Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Departments of
    2. Biochemistry and
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    • 2

      Medical Scientists of the Alberta Heritage Foundation for Medical Research.

    • 3

      Holder of the Canada Research Chair in Molecular and Cell Biology of Lipids.

  • Robert B. Campenot,

    1. Cell Biology, University of Alberta, Edmonton, Alberta, Canada
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    • 2

      Medical Scientists of the Alberta Heritage Foundation for Medical Research.

  • Jean E. Vance

    1. Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Departments of
    2. Medicine,
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Address correspondence and reprint requests to Dr Jean E. Vance, 332 Heritage Medical Research Center, University of Alberta, Edmonton Alberta T6G 2S2, Canada. E-mail: jean.vance@ualberta.ca

Abstract

Niemann–Pick type-C (NPC) disease is characterized by a progressive loss of neurons and an accumulation of unesterified cholesterol within the endocytic pathway. Unlike other tissues, however, NPC1-deficient brains do not accumulate cholesterol but whether or not NPC1-deficient neurons accumulate cholesterol is not clear. Therefore, as most studies on cholesterol homeostasis in NPC1-deficient cells have been performed in fibroblasts we have investigated cholesterol homeostasis in cultured murine sympathetic neurons lacking functional NPC1. These neurons did not display obvious abnormalities in growth or morphology and appeared to respond normally to nerve growth factor. Filipin staining revealed numerous cholesterol-filled endosomes/lysosomes in NPC1-deficient neurons and the mass of cholesterol in cell bodies was greater than in wild-type neurons. Surprisingly, however, the cholesterol content of NPC1-deficient and wild-type neurons as a whole was the same. This apparent paradox was resolved when the cholesterol content of NPC1-deficient distal axons was found to be less than of wild-type axons. Cholesterol sequestration in cell bodies did not depend on exogenously supplied cholesterol since the cholesterol accumulated before birth and did not disperse when neurons were cultured without exogenous cholesterol. The altered cholesterol distribution between cell bodies and axons suggests that transport of cholesterol, particularly that synthesized endogenously, from cell bodies to distal axons is impaired in NPC1-deficient neurons.

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