Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: Revisited
Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: Revisited
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DOI：
10.1523/jneurosci.3089-04.2005
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发表时间：
2005-03-02
影响因子：
5.3
通讯作者：
Sisodia, SS
中科院分区：
文献类型：
--
作者：
Lazarov, O;Morfini, GA;Sisodia, SS
β-APP裂解酶1（BACE 1）、早老素（PS）和γ-分泌酶复合物的其他蛋白质的连续酶促作用从称为β-淀粉样前体蛋白（APP）的较大的完整膜蛋白释放β-淀粉样蛋白（Abeta）肽。关于APP的正常功能或APP经历蛋白水解加工的神经元隔室的了解相对较少。最近的研究已被解释为与APP作为驱动蛋白-1货物受体的想法一致，PS和BACE 1与APP驻留的膜货物进行快速轴突运输。在这份报告中，来自几个独立的实验室之间的合作，我们研究了潜在的协会APP和驱动蛋白-1谷胱甘肽S-转移酶下拉和免疫共沉淀试验。此外，我们评估了运输的膜蛋白在坐骨神经的转基因小鼠与杂合或纯合缺失的APP。在以前的报告相反，我们无法找到证据APP和驱动蛋白-1之间的直接相互作用。此外，以前报道需要APP的驱动蛋白-1和酪氨酸激酶受体的转运在APP缺陷小鼠的轴突中没有变化。最后，我们发现APP蛋白水解机制的两个组成部分，即，PS1和BACE 1在小鼠坐骨神经中不与APP共转运。这些研究结果表明，假设APP作为驱动蛋白-1受体，并负责产生Abeta的蛋白水解加工机械在外周神经轴突中的相同囊泡隔室中运输，需要修订。
The sequential enzymatic actions of beta-APP cleaving enzyme 1 ( BACE1), presenilins ( PS), and other proteins of the gamma-secretase complex liberate beta-amyloid (Abeta) peptides from larger integral membrane proteins, termed beta-amyloid precursor proteins (APPs). Relatively little is known about the normal function(s) of APP or the neuronal compartment( s) in which APP undergoes proteolytic processing. Recent studies have been interpreted as consistent with the idea that APP serves as a kinesin-1 cargo receptor and that PS and BACE1 are associated with the APP-resident membranous cargos that undergo rapid axonal transport. In this report, derived from a collaboration among several independent laboratories, we examined the potential associations of APP and kinesin-1 using glutathione S-transferase pull-down and coimmunoprecipitation assays. In addition, we assessed the trafficking of membrane proteins in the sciatic nerves of transgenic mice with heterozygous or homozygous deletions of APP. In contrast to previous reports, we were unable to find evidence for direct interactions between APP and kinesin-1. Furthermore, the transport of kinesin-1 and tyrosine kinase receptors, previously reported to require APP, was unchanged in axons of APP-deficient mice. Finally, we show that two components of the APP proteolytic machinery, i.e., PS1 and BACE1, are not cotransported with APP in the sciatic nerves of mice. These findings suggest that the hypothesis that APP serves as a kinesin-1 receptor and that the proteolytic processing machinery responsible for generating Abeta is transported in the same vesicular compartment in axons of peripheral nerves requires revision.