Presenilin/γ-secretase regulates neurexin processing at synapses.
Presenilin/γ-secretase regulates neurexin processing at synapses.
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DOI：
10.1371/journal.pone.0019430
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Scholl FG
中科院分区：
文献类型：
--
作者：
Saura CA;Servián-Morilla E;Scholl FG
神经毒素是神经元质膜蛋白的一个大家族，其在突触分化期间作为跨突触受体起作用。已经提出突触前神经毒素与突触后伴侣（例如神经配蛋白）的结合参与调节突触形成/稳定的信号传导途径。与自闭症和精神发育迟滞相关的neurexin基因突变的鉴定表明，neurexins功能障碍可能是与大脑疾病相关的突触缺陷的基础。然而，调节neurexin在突触功能的机制仍不清楚。在这里，我们表明，neurexins的早老素（PS），γ-分泌酶复合物，介导的几个I型膜蛋白的膜内裂解的催化组分进行蛋白水解加工。通过药理学和遗传学方法抑制PS/γ-分泌酶可诱导培养的大鼠海马神经元和小鼠脑中神经节苷脂C-末端片段（CTFs）的大量积累。Neurexin-CTFs主要在PS条件性双敲除（PS cDKO）小鼠的突触前末梢处积累，所述PS条件性双敲除（PS cDKO）小鼠在前脑的突触能神经元中缺乏两种PS基因。PS功能的丧失增强了neurexin在由neuroligin-1介导的突触能末梢的积聚，这一事实表明PS调节neurexins在突触能突触的加工。有趣的是，早老素1（PS1）被神经连接素-1介导募集到神经元能末端，从而使PS1集中在含有β-neurexins的末端。此外，家族性阿尔茨海默病（FAD）相关的PS1突变差异影响β-neurexin-1加工。PS−/−细胞中PS1 M146 L和PS1 H163 R突变体的表达挽救了β-neurexin-1的加工，而PS1 C410 Y和PS1 ΔE9未能挽救加工缺陷。这些结果表明，PS调节突触的功能和加工的neurexins在突触能突触，和PS受损neurexin加工可能在FAD中发挥作用。
Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic neurexins to postsynaptic partners, such as neuroligins, has been proposed to participate in a signaling pathway that regulates synapse formation/stabilization. The identification of mutations in neurexin genes associated with autism and mental retardation suggests that dysfunction of neurexins may underlie synaptic defects associated with brain disorders. However, the mechanisms that regulate neurexin function at synapses are still unclear. Here, we show that neurexins are proteolytically processed by presenilins (PS), the catalytic components of the γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-secretase by using pharmacological and genetic approaches induces a drastic accumulation of neurexin C-terminal fragments (CTFs) in cultured rat hippocampal neurons and mouse brain. Neurexin-CTFs accumulate mainly at the presynaptic terminals of PS conditional double knockout (PS cDKO) mice lacking both PS genes in glutamatergic neurons of the forebrain. The fact that loss of PS function enhances neurexin accumulation at glutamatergic terminals mediated by neuroligin-1 suggests that PS regulate the processing of neurexins at glutamatergic synapses. Interestingly, presenilin 1 (PS1) is recruited to glutamatergic terminals mediated by neuroligin-1, thus concentrating PS1 at terminals containing β-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect β-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS−/− cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 fail to rescue the processing defect. These results suggest that PS regulate the synaptic function and processing of neurexins at glutamatergic synapses, and that impaired neurexin processing by PS may play a role in FAD.
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