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J. Biol. Chem. 275 (26): 20179-20187

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Embryonic Striatal Neurons from Niemann-Pick Type C Mice Exhibit Defects in Cholesterol Metabolism and Neurotrophin Responsiveness*

Leslie P. HendersonDagger §, Li LinDagger , Anita PrasadDagger , Colleen A. Paul§, Ta Yuan Chang§, and Robert A. MaueDagger §

From the Departments of Dagger  Physiology and § Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755

Niemann-Pick type C (NP-C) disease is a progressive and fatal neuropathological disorder previously characterized by abnormal cholesterol metabolism in peripheral tissues. Although a defective gene has been identified in both humans and the npcnih mouse model of NP-C disease, how this leads to abnormal neuronal function is unclear. Here we show that whereas embryonic striatal neurons from npcnih mice can take up low density lipoprotein-derived cholesterol, its subsequent hydrolysis and esterification are significantly reduced. Given the importance of cholesterol to a variety of signal transduction mechanisms, we assessed the effect of this abnormality on the ability of these neurons to respond to brain-derived neurotrophic factor (BDNF). In contrast to its effects on wild type neurons, BDNF failed to induce autophosphorylation of the TrkB receptor and to increase neurite outgrowth in npcnih neurons, despite expression of TrkB on the cell surface. The results suggest that abnormal cholesterol metabolism occurs in neurons in the brain during NP-C disease, even at embryonic stages of development prior to the onset of phenotypic symptoms. Moreover, this defect is associated with a lack of TrkB function and BDNF responsiveness, which may contribute to the loss of neuronal function observed in NP-C disease.

* This work was supported by grants from the Ara Parseghian Medical Research Foundation (to R. A. M., L. P. H., and T. Y. C.) and the National Niemann-Pick Disease Foundation (to L. P. H.).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.

To whom correspondence should be addressed: Dept. of Physiology, Dartmouth Medical School, Hanover, NH 03755. Tel.: 603-650-1311; Fax: 603-650-1128; E-mail: robert.maue@dartmouth.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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