Requirement for Neurotrophin Signal

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Science  14 Jul 2000:
Vol. 289, Issue 5477, pp. 219
DOI: 10.1126/science.289.5477.219c

Death from Niemann-Pick type C (NP-C) disease is caused by progressive neurodegeneration. The gene mutated in NP-C is thought to be involved in regulating cholesterol metabolism, and cholesterol is important for the formation of lipid rafts that have been suggested to be sites of organization of signal transduction complexes in the plasma membrane. Henderson et al. find that cholesterol metabolism in neurons from npcnih mice (a model for the human disease) is deficient and that these cells no longer exhibit neurite outgrowth in response to brain-derived neurotrophic factor (BDNF), which in normal cells binds to the TrkB receptor and induces its autophosphorylation. The lack of response to BDNF could be mimicked in wild-type cells by depleting the cells of cholesterol, strengthening the idea that cholesterol plays an important role in promoting cell signaling in response to neurotrophic factors. The data provide a mechanistic link between altered cholesterol metabolism and neurodegeneration, and may offer a clue to the connection between apolipoprotein E alleles and Alzheimer's disease. — NG

J. Biol. Chem. 275, 20179 (2000).

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