APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle.
APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle.
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DOI：
10.1523/jneurosci.1546-09.2009
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发表时间：
2009-11-18
期刊：
影响因子：
--
通讯作者：
Kins S
中科院分区：
文献类型：
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作者：
Szodorai A;Kuan YH;Hunzelmann S;Engel U;Sakane A;Sasaki T;Takai Y;Kirsch J;Müller U;Beyreuther K;Brady S;Morfini G;Kins S
淀粉样前体蛋白（APP）可能会被β-和γ-分泌酶依次切割，导致Aβ肽在阿尔茨海默病患者的大脑中积聚。α-分泌酶的切割阻止Aβ的产生。APP是由传统的驱动蛋白在一个独特的运输囊泡顺行运输，但这样的囊泡的生化组成，以及具体的驱动蛋白-1电机负责运输的定义很差。在这里，我们表明，通过延时分析和免疫分离，APP是一个货物的囊泡含有驱动蛋白重链亚型驱动蛋白-1C，小GTADRab 3A和突触前蛋白组分的一个特定子集。此外，我们报告说，驱动蛋白-1C和APP在这种囊泡类型的装配需要Rab 3A GTdR活性。最后，我们显示了在所分析的转运囊泡中APP通过α-分泌酶活性裂解，可能由ADAM 10介导。总之，这些数据首次表明，成熟的运输囊泡，包括传统的驱动蛋白的耦合，需要Rab GTdase活性。
The amyloid precursor protein (APP) may be sequentially cleaved by β- and γ-secretases leading to accumulation of Aβ peptides in brains of Alzheimer’s Disease patients. Cleavage by α-secretase prevents Aβ generation. APP is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle as well as the specific kinesin-1 motor responsible for transport are poorly defined. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A and a specific subset of presynaptic protein components. Moreover, we report that assembly of kinesin-1C and APP in this vesicle type requires Rab3A GTPase activity. Finally, we show cleavage of APP in the analyzed transport vesicles by α-secretase activity, likely mediated by ADAM10. Together, these data indicate for the first time that maturation of transport vesicles, including coupling of conventional kinesin, requires Rab GTPase activity.