Mitogen-activated protein kinase activity may not be necessary for the neuropathology of Niemann-Pick type C mice.
Mitogen-activated protein kinase activity may not be necessary for the neuropathology of Niemann-Pick type C mice.
复制标题
丝裂原激活蛋白激酶活性对于 Niemann-Pick C 型小鼠的神经病理学可能不是必需的。
DOI：
10.1111/j.1471-4159.2008.05657.x
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发表时间：
2008
影响因子：
4.7
通讯作者：
Vincent,Inez
中科院分区：
文献类型：
--
作者：
Zhang,Min;Hallows,JaniceL;Wang,Xuezhen;Bu,Bitao;Wang,Wei;Vincent,Inez
神经丝和tau蛋白的过度磷酸化以及细胞骨架病变的形成是几种人类神经退行性疾病的显著特征，包括C型尼曼匹克病（NPC）。以往的研究表明，MAPK、细胞外信号调节激酶1和2（ERK 1/2）在鼻咽癌的发生发展中起重要作用。为了验证这一想法，我们用PD 98059（一种特异性和有效的MAPK激活抑制剂）治疗NPC小鼠。尽管ERK 1/2的活性被抑制了40%，但在NPC小鼠细胞骨架病理和症状发作前2周侧脑室输注PD 98059并没有延迟或抑制NPC的突出特征。出乎意料的是，ERK 1/2抑制导致tau过度磷酸化的加重，特别是在少突胶质细胞中，其方式与某些人类tau蛋白病相似。我们的研究结果表明，ERK 1/2在NPC神经病理学中不起主要作用，因此，MAPK抑制不太可能是一个有用的策略来管理疾病。
Hyperphosphorylation of neurofilament and tau, and formation of cytoskeletal lesions, are notable features of several human neurodegenerative diseases, including Niemann‐Pick Disease Type C (NPC). Previous studies suggested that the MAPKs, extracellular signal regulated kinase 1 and 2 (ERK1/2) may play a significant role in this aspect of NPC. To test this idea, we treated npc mice with PD98059, a specific and potent inhibitor of MAPK activation. Although activity of ERK1/2 was inhibited by 40%, a 2‐week intracerebroventricular infusion of PD98059 just prior to onset of cytoskeletal pathology and symptoms in npc mice did not delay or inhibit prominent hallmarks of NPC. Unexpectedly, ERK1/2 inhibition led to aggravation of tau hyperphosphorylation, particularly in oligodendroctyes, in a manner similar to that of certain human tauopathies. Our results suggest that ERK1/2 does not play a major role in NPC neuropathology, and therefore, that MAPK inhibition is unlikely to be a useful strategy for managing the disease.