Embryonic striatal neurons from niemann-pick type C mice exhibit defects in cholesterol metabolism and neurotrophin responsiveness.

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 npc(nih) mouse model of NP-C disease, how this leads to abnormal neuronal function is unclear. Here we show that whereas embryonic striatal neurons from npc(nih) 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 npc(nih) 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.