Trinity College Institute of Neuroscience, School of Genetics and Microbiology, Smurfit Institute of Genetics and School of Natural Sciences, Trinity College Dublin, Dublin, Ireland.
School of Biosciences and Bioengineering, Indian Institute of Technology, Mandi, India.
PLoS Genet. 2024 May 20;20(5):e1011251. doi: 10.1371/journal.pgen.1011251. eCollection 2024 May.
Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.
共济失调蛋白 2（ATXN2）是一种与脊髓小脑共济失调 2 型（SCA2）、肌萎缩侧索硬化症（ALS）和帕金森病相关的基因。编码的蛋白是 ALS 和相关疾病的治疗靶点。ATXN2（或昆虫中的 Atx2）可以在翻译激活、翻译抑制、mRNA 稳定性以及 mRNP 颗粒的组装中发挥作用，这个过程由无序区域（IDR）介导。先前的工作表明，Atx2 的 LSm（类似 Sm）结构域可以帮助刺激 mRNA 翻译，拮抗 mRNP 颗粒的组装。在这里，我们通过一系列果蝇和人类 Ataxin-2 蛋白的实验推进了这些发现。RNA 结合蛋白靶标鉴定（TRIBE）、共定位和免疫沉淀实验的结果表明，与多聚 A 结合蛋白（PABP）相互作用的 Ataxin-2 的 PAM2 基序可能是 Ataxin-2 mRNP 颗粒中 mRNA 和蛋白含量的主要决定因素。利用转基因果蝇的实验表明，尽管 Atx2-LSm 结构域可能有助于预防神经退行性变，但结构化的 PAM2 和非结构化的 IDR 相互作用都支持 Ataxin-2 诱导的细胞毒性。总之，这些数据提出了一个假设，即 Ataxin-2 的相互作用在翻译调控过程中是如何重塑的，以及结构化和非结构化相互作用如何在 RNP 颗粒凝聚的特异性和效率以及神经退行性变方面产生不同的影响。
