School of Genetics and Microbiology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
School of Basic Science, Indian Institute of Technology, Mandi, Suran 175075, India.
G3 (Bethesda). 2021 Dec 8;11(12). doi: 10.1093/g3journal/jkab355.
The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson's disease, and Huntington's disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here, we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesized, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington's disease and, potentially, other proteinopathies.
Ataxin-2 (Atx2) 蛋白有助于肌萎缩侧索硬化症 (ALS)、2 型脊髓小脑共济失调 (SCA-2)、帕金森病和亨廷顿病 (HD) 的动物模型中神经退行性表型的进展。然而，由于 Atx2 蛋白包含多个可分离的活性，因此更深入的理解需要进行实验以确定 Atx2 调节神经退行性变 (ND) 进展的确切机制。最近在果蝇中的两种 ALS 模型 C9ORF72 和 FUS 的研究表明，Atx2 蛋白的 C 端固有无序区 (cIDR) 是组装核糖核蛋白 (RNP) 颗粒所必需的，这对于神经退行性表型的进展以及与这些 ALS 模型相关的蛋白质包涵体的积累都是必不可少的。在这里，我们表明 Atx2-cIDR 也同样有助于 HD 的果蝇模型中退行性表型的进展和 Huntingtin 蛋白聚集体的积累。由于 Huntingtin 不是 RNP 颗粒的既定组成部分，这些观察结果支持了最近提出的、意想不到的 RNP 颗粒的蛋白质处理功能假说，这可能有助于亨廷顿病的进展，并可能有助于其他蛋白质病。
