Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2.
Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2.
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DOI：
10.1016/j.cub.2015.06.045
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发表时间：
2015-08-17
期刊：
影响因子：
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通讯作者：
Freeman MR
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文献类型：
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作者：
Sreedharan J;Neukomm LJ;Brown RH Jr;Freeman MR
RNA加工蛋白TDP-43是肌萎缩侧索硬化症（ALS）的发病机制的核心，ALS是最常见的成人发作的运动神经元（MN）疾病。TDP-43在果蝇中是保守的，在果蝇中它一直是大量研究的主题，但TDP-43突变如何导致年龄依赖性神经退行性变尚不清楚，大多数方法都没有直接检查MN形态随年龄的变化。我们使用马赛克的方法来研究年龄依赖性MN损失的成年苍蝇腿，它是可能的，以解决单一的运动轴突，NMJs和活动区，并进行快速向前遗传筛选。我们发现TDP-43 Q331 K的表达引起了NMJ和轴突的回退，这不能被阻断沃勒变性的突变所抑制。我们报告了三个抑制TDP-43毒性的基因的鉴定，包括Shaggy/GSK 3，一种已知的神经变性修饰剂。另外两个新的抑制因子，帽子戏法和Xmas-2，在染色质建模和RNA输出中起作用，这两个过程最近与人类ALS有关。Shaggy/GSK 3、Hat-trick或Xmas-2的缺失不能抑制沃勒变性，认为TDP-43 Q331 K诱导的和沃勒变性是遗传上不同的过程。除了描绘修改TDP-43毒性的遗传因素，这些结果建立了果蝇成年腿作为一个有价值的新工具，在体内研究成人MN表型。
The RNA processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease. TDP-43 is conserved in Drosophila, where it has been the topic of considerable study, but how TDP-43 mutations lead to age-dependent neurodegeneration is unclear and most approaches have not directly examined changes in MN morphology with age. We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens. We show that expression of TDP-43Q331K caused dying-back of NMJs and axons, which could not be suppressed by mutations that block Wallerian degeneration. We report the identification of three genes that suppress TDP-43 toxicity, including Shaggy/GSK3, a known modifier of neurodegeneration. The two additional novel suppressors, Hat-trick and Xmas-2, function in chromatin modeling and RNA export, two processes recently implicated in human ALS. Loss of Shaggy/GSK3, Hat-trick or Xmas-2 does not suppress Wallerian degeneration, arguing TDP-43Q331K-induced and Wallerian degeneration are genetically distinct processes. In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes.