Kinesin light chain-1 variant E disrupts axonal transport and Aβ generation in Alzheimer's disease (comment on DOI 10.1002/bies.201400131).
Kinesin light chain-1 variant E disrupts axonal transport and Aβ generation in Alzheimer's disease (comment on DOI 10.1002/bies.201400131).
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驱动蛋白轻链 1 变体 E 破坏阿尔茨海默病中的轴突运输和 Aβ 生成（DOI 10.1002/bies.201400131 的评论）。
DOI：
10.1002/bies.201400206
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Potter,Huntington
中科院分区：
文献类型：
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作者：
Potter,Huntington
虽然许多研究表明神经退行性疾病中快速轴突运输被破坏，但导致这种破坏的机制和因果箭头的方向尚不清楚。例如，APP或早老素基因中家族性阿尔茨海默病致病突变的表达，或细胞暴露于ps依赖性APP裂解产物（Aβ肽）中，会损害轴突运输，包括APP蛋白本身的运输。最近，Morihara及其同事对不同背景下携带APP转基因的小鼠菌株进行转录组分析，以发现它们不同水平的a β积累[1]的原因。他们发现，运动蛋白轻链-1剪接变体E （KLC1vE）是a β积累的修饰因子，并且在阿尔茨海默病大脑中过度表达。此外，神经母细胞瘤细胞中KLC1vE的过表达或敲低分别增加或减少Aβ的产生。在Gan等人发表的最新论文《Atlas: Kinesin轻链-1变体E引发阿尔茨海默病轴突运输中断和淀粉样蛋白β生成的恶性循环》中，该团队的三位成员对有关Kinesin轻链结构和功能以及微管参与神经变性的文献进行了深刻而全面的回顾，特别关注轴突运输[2]。然后，他们提出并讨论了KLC1vE如何改变Aβ积累并促进阿尔茨海默病病理和痴呆的三个不相互排斥的假设。具体:
Although many studies have shown that fast axonal transport is disrupted in neurodegenerative diseases, mechanism (s) leading to the disruption and the direction of the cause↔ effect arrow have been unclear. For example, expression of Familial Alzheimer’s Disease-causing mutations in APP or Presenilin genes, or exposure of cells to the product of PS-dependent APP cleavage—the Aβ peptide—impairs axonal transport, including that of APP protein itself. Recently, Morihara and colleagues used transcriptome analysis of various mouse strains, each carrying an APP transgene in a different background, to discover the reasons for their different levels of Aβ accumulation [1]. They found that kinesin light chain-1 splice variant E (KLC1vE) is a modifier of Aβ accumulation, and is overexpressed in Alzheimer’s disease brain. Furthermore, overexpression or knockdown of KLC1vE in neuroblastoma cells increases or decreases production of Aβ, respectively. In the current paper “Atlas stumbled: Kinesin light chain-1 variant E triggers a vicious cycle of axonal transport disruption and amyloid-β generation in Alzheimer’s disease” by Gan et al., three members of the team provide an insightful and thorough review of the literature on kinesin light chain structure and function and on microtubule involvement in neurodegeneration, with particular focus on axonal transport [2]. They then present and discuss three nonmutually exclusive hypotheses for how KLC1vE may alter Aβ accumulation and contribute to Alzheimer’s disease pathology and dementia. Specifically: