Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo
Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo
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DOI：
10.1093/hmg/ddt237
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发表时间：
2013-10-01
影响因子：
3.5
通讯作者：
Goldstein, Lawrence S. B.
中科院分区：
文献类型：
--
作者：
Gunawardena, Shermali;Yang, Ge;Goldstein, Lawrence S. B.
神经元和其他细胞需要细胞内运输重要成分以维持活力和功能。先前的工作表明，虽然净淀粉样前体蛋白（APP）运输通常是顺行的，但含有APP的单个囊泡双向移动。这种差异突出了我们对APP-囊泡运输的体内调节的理解不足。在这里，我们表明，减少早老素（PS）或抑制γ-分泌酶活性大大增加APP囊泡的顺行和逆行速度。引人注目的是，PS缺陷对含有突触结合蛋白的不相关的货物囊泡类没有影响，该囊泡类由不同的驱动蛋白马达提供动力。PS或γ-分泌酶减少引起的速度增加需要功能性驱动蛋白-1和动力蛋白马达。总之，我们的研究结果表明，PS的正常功能是抑制驱动蛋白-1和动力蛋白的运动活动在轴突运输的APP囊泡。此外，我们的数据表明，轴突运输缺陷引起的PS介导的APP-囊泡运动的调节作用的损失可能是阿尔茨海默病（AD）发病机制中观察到的神经元和突触缺陷的主要原因。因此，APP/PS转运的扰动可能有助于在AD中观察到的早期神经病理学，并突出了在神经元损失和疾病的临床表现之前进行早期干预的潜在新治疗途径。
Neurons and other cells require intracellular transport of essential components for viability and function. Previous work has shown that while net amyloid precursor protein (APP) transport is generally anterograde, individual vesicles containing APP move bi-directionally. This discrepancy highlights our poor understanding of the in vivo regulation of APP-vesicle transport. Here, we show that reduction of presenilin (PS) or suppression of gamma-secretase activity substantially increases anterograde and retrograde velocities for APP vesicles. Strikingly, PS deficiency has no effect on an unrelated cargo vesicle class containing synaptotagmin, which is powered by a different kinesin motor. Increased velocities caused by PS or gamma-secretase reduction require functional kinesin-1 and dynein motors. Together, our findings suggest that a normal function of PS is to repress kinesin-1 and dynein motor activity during axonal transport of APP vesicles. Furthermore, our data suggest that axonal transport defects induced by loss of PS-mediated regulatory effects on APP-vesicle motility could be a major cause of neuronal and synaptic defects observed in Alzheimer's Disease (AD) pathogenesis. Thus, perturbations of APP/PS transport could contribute to early neuropathology observed in AD, and highlight a potential novel therapeutic pathway for early intervention, prior to neuronal loss and clinical manifestation of disease.