Snapin-mediated BACE1 retrograde transport is essential for its degradation in lysosomes and regulation of APP processing in neurons.
Snapin-mediated BACE1 retrograde transport is essential for its degradation in lysosomes and regulation of APP processing in neurons.
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DOI：
10.1016/j.celrep.2013.12.008
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发表时间：
2014-01-16
期刊：
影响因子：
8.8
通讯作者：
Cai Q
中科院分区：
文献类型：
--
作者：
Ye X;Cai Q
β-淀粉样前体蛋白（APP）裂解酶1（BACE 1）是产生淀粉样β（Aβ）肽的主要β-分泌酶。内体的酸性环境对于β-分泌酶活性是最佳的。然而，调节BACE 1从内体运输到溶酶体以进行降解的机制在很大程度上是未知的。在这里，使用Snapin缺陷小鼠结合基因拯救实验，我们发现，Snapin，作为一个动力蛋白马达适配器晚期内体，介导BACE 1逆行运输。hAPP突变体活神经元和小鼠脑表现出BACE 1在改变的晚期内吞细胞器内的积累和由于Snapin-动力蛋白偶联减少而导致的溶酶体靶向缺陷。删除Snapin或破坏Snapin-dynein偶联减少BACE 1转运到溶酶体降解，从而增强APP加工。在hAPP神经元中过表达Snapin通过增强BACE 1周转减少APP的β位点切割。总而言之，我们的研究为BACE 1水平/活性的复杂调节和通过逆行转运的周转提供了新的机制见解，从而控制了神经元中的Aβ生成。
β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major β-secretase for generating amyloid-β (Aβ) peptides. The acidic environment of endosomes is optimal for β-secretase activity. However, the mechanisms regulating BACE1 traffic from endosomes to lysosomes for degradation are largely unknown. Here, using snapin-deficient mice combined with gene rescue experiments, we reveal that Snapin, as a dynein motor adaptor for late endosomes, mediates BACE1 retrograde transport. hAPP mutant live neurons and mouse brains exhibited BACE1 accumulation within the altered late endocytic organelles and defective lysosomal targeting due to reduced Snapin-dynein coupling. Deleting snapin or disrupting Snapin-dynein coupling reduces BACE1 transport to lysosomes for degradation, thus enhancing APP processing. Overexpressing Snapin in hAPP neurons reduces β-site cleavage of APP by enhancing BACE1 turnover. Altogether, our study provides new mechanistic insights into the complex regulation of BACE1 level/activity and turnover through retrograde transport, thus controlling Aβ generation in neurons.
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DOI：
10.1523/jneurosci.6473-11.2012
发表时间：
2012-08-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
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