Cell signaling abnormalities may drive neurodegeneration in familial Alzheimer disease.
Cell signaling abnormalities may drive neurodegeneration in familial Alzheimer disease.
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DOI：
10.1007/s11064-013-1003-6
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发表时间：
2014
影响因子：
4.4
通讯作者：
Robakis, Nikolaos K.
中科院分区：
文献类型：
--
作者：
Robakis, Nikolaos K.
早老素（Presenilins，PS）是γ-分泌酶复合物的催化组分，可产生Aβ肽。γ-分泌酶的底物是由细胞表面蛋白的胞外序列裂解产生的膜结合蛋白片段。APP衍生的γ-分泌酶底物在γ（γ）位点裂解产生Aβ，而在ε（ε）位点裂解产生AICD，推测其在转录中起作用。除APP外，γ-分泌酶还促进大量细胞表面蛋白的ε-裂解，产生显示在细胞信号传导中起作用的胞质肽。一种常见的假说认为阿尔茨海默病（AD）是由Aβ肽或其产物引起的。然而，用Aβ产生抑制剂治疗患者，在诱导细胞毒性的同时没有显示出治疗益处。同样，抗A β抗体治疗也产生了令人失望的结果。重要的是，最近的证据表明，PS FAD突变导致底物ε位点的γ-分泌酶切割活性丧失，从而抑制生物学上重要的细胞信号肽的产生，同时促进膜结合细胞毒性底物的积累。这些数据支持以下假设：FAD突变可能通过抑制γ-分泌酶催化的底物ε裂解，从而干扰细胞信号传导，同时还促进细胞毒性肽的蓄积，从而增加神经毒性。类似的机制可以解释临床试验中观察到的γ-分泌酶相关毒性。在这里，我们讨论的证据表明，FAD神经变性可能是由于γ-分泌酶裂解功能的基板ε网站的损失。
Presenilins (PSs) are catalytic components of the γ-secretase complex that produces Aβ peptides. Substrates of γ-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived γ-secretase substrates are cleaved at gamma (γ) sites to produce Aβ while cleavage at the epsilon (ε) site produces AICD proposed to function in transcription. In addition to APP, γ-secretase promotes the ε-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling. A common hypothesis suggests that Alzheimer's disease (AD) is caused by Aβ peptides or their products. Treatment of patients with inhibitors of Aβ production however, showed no therapeutic benefits while inducing cytotoxicity. Similarly, treatments with anti-Aβ antibodies yielded disappointing results. Importantly, recent evidence shows that PS FAD mutations cause a loss of γ-secretase cleavage activity at ε site of substrates thus inhibiting production of biologically important cell signaling peptides while promoting accumulation of membrane-bound cytotoxic substrates. These data support a hypothesis that FAD mutations may increase neurotoxicity by inhibiting the γ-secretase-catalyzed ε cleavage of substrates thus interfering with cell signaling while also promoting accumulation of cytotoxic peptides. Similar mechanisms may explain γ-secretase inhibitor-associated toxicities observed in clinical trials. Here we discuss evidence that FAD neurodegeneration may be caused by loss of γ-secretase cleavage function at ε sites of substrates.
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影响因子：
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发表时间：
1999-03-16
影响因子：
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通讯作者：
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