Bace1 modulates myelination in the central and peripheral nervous system
Bace1 modulates myelination in the central and peripheral nervous system
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DOI：
10.1038/nn1797
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发表时间：
2006-12-01
影响因子：
25
通讯作者：
Yan, Riqiang
中科院分区：
文献类型：
--
作者：
Hu, Xiangyou;Hicks, Caitlin W.;Yan, Riqiang
Bace1 是一种肽链内切酶，可在 β 分泌酶位点裂解淀粉样前体蛋白。除了这种切割之外，Bace1 在其他生理事件中的功能重要性尚不清楚。我们在此表明，Bace1 调节中枢神经和周围神经的髓鞘形成过程和髓鞘厚度。在Bace1缺失小鼠中，髓鞘形成过程延迟，髓鞘厚度明显减少，表明Bace1基因缺失导致髓鞘形成低下。 Bace1缺失小鼠还表现出神经行为改变，例如疼痛敏感性升高和握力降低。进一步的机制研究表明，Bace1 缺失小鼠的神经调节蛋白-Akt 信号通路发生了改变。 Bace1 缺失小鼠的 CNS 中全长 neregulin-1 增加，其裂解产物减少。此外，磷酸化的 Akt 也被减少。基于这些和之前的研究，我们假设神经元富集的 Bace1 裂解 neregulin-1，并且加工后的 neregulin-1 通过髓磷脂形成细胞中 Akt 的磷酸化来调节髓鞘形成。
Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the beta-secretase site. Apart from this cleavage, the functional importance of Bace1 in other physiological events is unknown. We show here that Bace1 regulates the process of myelination and myelin sheath thickness in the central and peripheral nerves. In Bace1-null mice, the process of myelination was delayed and myelin thickness was markedly reduced, indicating that genetic deletion of Bace1 causes hypomyelination. Bace1-null mice also showed altered neurological behaviors such as elevated pain sensitivity and reduced grip strength. Further mechanistic studies showed an altered neuregulin-Akt signaling pathway in Bace1-null mice. Full-length neuregulin-1 was increased and its cleavage product was decreased in the CNS of Bace1-null mice. Furthermore, phosphorylated Akt was also reduced. Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells.