National Centre for Biological Sciences, TIFR, Bangalore 560065, India.
Trinity College Institute of Neuroscience, School of Genetics and Microbiology, Smurfit Institute of Genetics and School of Natural Sciences, Trinity College Dublin, Dublin-2, Ireland.
Neuron. 2018 May 16;98(4):754-766.e4. doi: 10.1016/j.neuron.2018.04.032.
Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo. Remarkably, ΔIDR mutants that lack neuronal RNP granules show normal animal development, survival, and fertility. However, they show defects in long-term memory formation/consolidation as well as in C9ORF72 dipeptide repeat or FUS-induced neurodegeneration. Together, our findings demonstrate (1) that higher-order mRNP assemblies contribute to long-term neuronal plasticity and memory, and (2) that a targeted reduction in RNP-granule formation efficiency can alleviate specific forms of neurodegeneration.
人 Ataxin-2 与肌萎缩侧索硬化症（ALS）和 2 型脊髓小脑共济失调（SCA-2）的病因和进展有关。在果蝇中，保守的 atx2 基因对动物的生存以及正常的 RNP 颗粒组装、翻译控制和长期习惯形成是必不可少的。像其人类同源物一样，果蝇 Ataxin-2（Atx2）含有多聚 Q 重复和额外的固有无序区域（IDR）。我们证明，Atx2 IDR 能够在体外介导液-液相转变，对于体内神经元 mRNP 组装的有效形成是必不可少的。值得注意的是，缺失神经元 RNP 颗粒的ΔIDR 突变体显示出正常的动物发育、存活和生育能力。然而，它们在长期记忆形成/巩固以及 C9ORF72 二肽重复或 FUS 诱导的神经退行性变中表现出缺陷。总之，我们的研究结果表明：（1）更高阶的 mRNP 组装有助于长期的神经元可塑性和记忆；（2）靶向降低 RNP 颗粒形成效率可以缓解特定形式的神经退行性变。
