The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration.
The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration.
复制标题
β-淀粉样蛋白前体蛋白在分化、有丝分裂、应激和变性过程中通过不同的途径被磷酸化。
DOI：
10.1091/mbc.e06-07-0625
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发表时间：
2007
影响因子：
3.3
通讯作者：
Muresan,Virgil
中科院分区：
文献类型：
--
作者：
Muresan,Zoia;Muresan,Virgil
淀粉样蛋白-β前体蛋白（APP） thr668位点的磷酸化是一个与神经突延伸和水泡货物顺行运输相关的正常过程。相反，APP磷酸化增加是阿尔茨海默病的病理特征。在培养细胞中，APP在唐氏综合症中过度表达，这种情况偶尔会导致APP磷酸化增加。在正常和高APP条件下，APP的磷酸化是否通过相似或不同的信号通路发生尚不清楚。在这里，我们使用脑干来源的神经元（CAD细胞）解决了这个问题。异位过表达APP的CAD细胞常表现为神经元变性的特征。我们发现，在退行性细胞中，APP被过度磷酸化并与早期内体共定位。相比之下，在正常的CAD细胞中，磷酸化的APP （pAPP）被排除在核内体之外，并定位于高尔基体并在神经突内运输囊泡。神经鞘APP通过糖原合成酶激酶3β调节的途径被c-Jun nh2末端激酶磷酸化，而退化CAD细胞中的内体pAPP是由周期蛋白依赖性激酶5的激活引起的。导致APP磷酸化的其他信号通路在应激和有丝分裂期间变得活跃。我们得出结论，APP磷酸化的不同途径在增殖、分化、应激和退化的神经元中起作用。
Phosphorylation of amyloid-β precursor protein (APP) at Thr668is a normal process linked to neurite extension and anterograde transport of vesicular cargo. By contrast, increased phosphorylation of APP is a pathological trait of Alzheimer's disease. APP is overexpressed in Down's syndrome, a condition that occasionally leads to increased APP phosphorylation, in cultured cells. Whether phosphorylation of APP in normal versus high APP conditions occurs by similar or distinct signaling pathways is not known. Here, we addressed this problem using brainstem-derived neurons (CAD cells). CAD cells that ectopically overexpress APP frequently show features of degenerating neurons. We found that, in degenerating cells, APP is hyperphosphorylated and colocalizes with early endosomes. By contrast, in normal CAD cells, phosphorylated APP (pAPP) is excluded from endosomes, and localizes to the Golgi apparatus and to transport vesicles within the neurites. Whereas the neuritic APP is phosphorylated by c-Jun NH2-terminal kinase through a pathway that is modulated by glycogen synthase kinase 3β, the endosomal pAPP in degenerated CAD cells results from activation of cyclin-dependent kinase 5. Additional signaling pathways, leading to APP phosphorylation, become active during stress and mitosis. We conclude that distinct pathways of APP phosphorylation operate in proliferating, differentiating, stressed, and degenerating neurons.