Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity
Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity
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DOI：
10.1073/pnas.1605964113
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发表时间：
2016-10-11
影响因子：
11.1
通讯作者：
Xu, Zuoshang
中科院分区：
文献类型：
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作者：
Yang, Chunxing;Danielson, Eric W.;Xu, Zuoshang
profilin 1（PFN 1）基因突变会导致肌萎缩侧索硬化症（ALS），这是一种神经退行性疾病，由运动神经元丢失引起，导致瘫痪并最终死亡。PFN 1是一种小的肌动蛋白结合蛋白，促进基于formin的肌动蛋白聚合并调节许多细胞功能，但PFN 1突变如何导致ALS尚不清楚。为了研究这个问题，我们已经产生了表达ALS相关突变体（C71 G）或野生型蛋白的转基因小鼠。在这里，我们报告说，表达突变体而不是野生型蛋白质的小鼠具有运动神经元丧失的无情进展，伴随着进行性肌肉无力，最终导致瘫痪和死亡。此外，突变体，而不是野生型，PFN 1形成不溶性聚集体，破坏细胞骨架结构，并提高运动神经元中的泛素和p62/SQSTM水平。出乎意料的是，运动神经元变性的加速先于突变体PFN 1聚集体的积累。这些结果表明，虽然突变PFN 1聚集可能有助于神经变性，但它不会触发其发作。重要的是，这些实验建立了一个进行性疾病模型，有助于确定ALS发病机制和治疗方法的发展。
Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear. To investigate this problem, we have generated transgenic mice expressing either the ALS-associated mutant (C71G) or wild-type protein. Here, we report that mice expressing the mutant, but not the wild-type, protein had relentless progression of motor neuron loss with concomitant progressive muscle weakness ending in paralysis and death. Furthermore, mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset. Importantly, these experiments establish a progressive disease model that can contribute toward identifying the mechanisms of ALS pathogenesis and the development of therapeutic treatments.