Cholesterol Requirement for Neurotrophin Signals

Science's STKE  04 Jul 2000:
Vol. 2000, Issue 39, pp. tw1
DOI: 10.1126/stke.2000.39.tw1

Death from Niemann-Pick type C (NP-C) disease is caused by progressive neurodegeneration. The gene mutated in NP-C is involved the regulation of cholesterol metabolism. Cholesterol is important for the formation of lipid rafts that are postulated to be sites of organization of signaling complexes. Henderson et al. provide evidence for abnormal cholesterol metabolism in cultured neurons from npcnih mice that have a mutation in the NP-C gene that results in a phenotype resembling human NP-C disease. Furthermore, the mutant cells do not respond to the neurotrophin brain-derived neurotrophic factor (BDNF), which stimulates the TrkB receptor in these cells. The mutant cells neither exhibited tyrosine phosphorylation of the TrkB receptor nor responded to BDNF with an increase in neurite outgrowth. 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 extracellular factors. The data provide a mechanistic link between altered cholesterol metabolism and neurodegeneration.

Henderson, L.P., Lin, L., Prasad, A., Paul, C.A., Chang, T.Y., and Maue, R.A. (2000) Embryonic striatal neurons from Niemann-Pick type C mice exhibits defects in cholesterol metabolism and neurotrophin responsiveness. J. Biol. Chem. 275: 20179-20187. [Abstract] [Full Text]