Henderson L P, Lin L, Prasad A, Paul C A, Chang T Y, Maue R A
Departments of Physiology and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
J Biol Chem. 2000 Jun 30;275(26):20179-87. doi: 10.1074/jbc.M001793200.
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.
尼曼-匹克C型（NP-C）病是一种进行性致命性神经病理学疾病，以前其特征为外周组织中胆固醇代谢异常。尽管在人类和NP-C病的npc(nih)小鼠模型中都已鉴定出缺陷基因，但尚不清楚这是如何导致异常神经元功能的。在此我们表明，虽然来自npc(nih)小鼠的胚胎纹状体神经元能够摄取低密度脂蛋白衍生的胆固醇，但其随后的水解和酯化作用却显著降低了。鉴于胆固醇对多种信号转导机制的重要性，我们评估了这种异常对这些神经元响应脑源性神经营养因子（BDNF）能力的影响。与对野生型神经元的作用相反，尽管TrkB在细胞表面表达，但BDNF未能诱导npc(nih)神经元中TrkB受体的自磷酸化，也未能增加其神经突生长。结果表明，即使在NP-C病表型症状出现之前的胚胎发育阶段，大脑中的神经元也会发生异常胆固醇代谢。此外，这种缺陷与TrkB功能缺失和BDNF反应性缺乏有关，这可能导致NP-C病中观察到的神经元功能丧失。
