Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport.
Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport.
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DOI：
10.1091/mbc.e14-06-1111
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发表时间：
2014-11-05
影响因子：
3.3
通讯作者：
Suzuki T
中科院分区：
文献类型：
--
作者：
Chiba K;Araseki M;Nozawa K;Furukori K;Araki Y;Matsushima T;Nakaya T;Hata S;Saito Y;Uchida S;Okada Y;Nairn AC;Davis RJ;Yamamoto T;Kinjo M;Taru H;Suzuki T
APP通过JIP 1与驱动蛋白-1结合。在JIP 1基因缺失的神经元中，APP货物的快速和高频率的顺行运输分别被削弱为速度降低和频率降低。JIP 1与KLC通过JIP 1中的两个新元件相互作用，在有效的APP轴突运输中起着重要作用。阿尔茨海默氏病β-淀粉样前体蛋白（APP）通过JNK相互作用蛋白1（JIP 1）与驱动蛋白-1相关;然而，JIP 1在神经元中驱动蛋白-1转运APP中的作用仍不清楚。我们进行了定量分析，以了解JIP 1在APP轴突运输中的作用。在JIP 1缺陷的神经元中，我们发现APP货物的顺行运输的快速度（1.27 μm/s）和高频率（66%）都被削弱为降低的速度（1.83 μm/s）和较低的频率（45%）。我们确定了两个新的元件连接到JIP 1功能，位于JIP 1b的中心区域，与驱动蛋白轻链1（KLC 1）的卷曲螺旋结构域相互作用，除了传统的JIP 1b 11-氨基酸C-末端（C11）区域与KLC 1的tetratricopeptide重复的相互作用。APP的高频率顺行运输依赖于JIP 1b中的一个新元件。APP货物运输的快速速度需要C11结构域，该结构域由JIP 1b的第二个新区域调节。此外，有效的APP轴突运输不受APP在Thr-668磷酸化的影响，该位点已知被JNK磷酸化。我们的定量分析表明，在神经元中观察到的增强的快速和高效的高频APP顺行运输是由JIP 1b的新作用介导的。
APP associates with kinesin-1 via JIP1. In JIP1-decicient neurons, the fast velocity and high frequency of anterograde transport of APP cargo are impaired to reduced velocity and lower frequency, respectively. Interaction of JIP1 with KLC via two novel elements in JIP1 plays an important role in efficient APP axonal transport. Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (∼2.7 μm/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11–amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.