ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.
ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.
复制标题
DOI：
10.1038/ncomms10465
复制
发表时间：
2016-02-04
影响因子：
16.6
通讯作者：
Shneider NA
中科院分区：
文献类型：
--
作者：
Sharma A;Lyashchenko AK;Lu L;Nasrabady SE;Elmaleh M;Mendelsohn M;Nemes A;Tapia JC;Mentis GZ;Shneider NA
FUS突变导致肌萎缩侧索硬化症（ALS），包括一些最具侵略性的，青少年发病形式的疾病。FUS功能丧失和毒性功能获得机制已被提出来解释突变型FUS如何导致运动神经元变性，但在ALS的发病机制中均未确定。在这里，我们描述了一系列转基因FUS小鼠品系，表现出渐进的，依赖于肌肉的运动神经元变性之前，在神经肌肉接头的早期，结构和功能异常。一种新的条件性FUS基因敲除突变体揭示，出生后消除FUS对运动神经元存活或功能没有影响。此外，内源性FUS不有助于突变型FUS诱导的ALS表型的发作。这些发现表明，FUS依赖性运动退化不是由于FUS功能的丧失，而是由于ALS突变所赋予的毒性特性的获得。 FUS突变导致家族性ALS的机制尚不清楚。在这里，作者使用小鼠转基因模型来表明，毒性功能获得是运动神经元变性的基础，并且突变FUS的毒性不依赖于FUS活性的丧失或过量。
Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. The mechanism by which FUS mutations cause familial ALS remains unclear. Here, the authors use mouse transgenic models to show that a toxic gain-of-function underlies motor neuron degeneration, and that the toxicity of mutant FUS does not depend on a loss or excess of FUS activity.