Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport dysfunction and suppress local translation.
Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport dysfunction and suppress local translation.
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Ataxin-2 聚谷氨酰胺扩增异常地隔离 TDP-43，导致核糖核蛋白凝聚物转运功能障碍并抑制局部翻译。
DOI：
10.1101/2023.01.30.526372
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Gopal,PallaviP
中科院分区：
文献类型：
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作者：
Wijegunawardana,Denethi;Vishal,SonaliS;Venkatesh,Neha;Gopal,PallaviP
RNA代谢异常是家族性和散发性肌萎缩侧索硬化症(ALS)的常见致病机制。ALS的特征是TDP-43的错误定位和聚集，TDP-43是一种RNA结合蛋白(RBP)，在转录后RNA加工中具有多种作用。最近的研究已经发现TDP-43和Aaxin-2之间的遗传相互作用，Aaxin-2是一种多谷氨酰胺(PolyQ)RBP，在这种RBP中，中等长度的PolyQ扩张会增加ALS的风险。在这里，我们使用活细胞共聚焦成像、光漂白和翻译报告分析来研究TDP-43/Aaxin-2在啮齿动物原代皮质神经元中的定位、转运动力学和mRNA调节功能。我们发现，Aaxin-2的PolyQ扩张异常地将TDP-43隔离在核糖核蛋白(RNP)凝聚体中，并破坏了其沿轴突的运动性和类液体性质。我们的数据表明，Aaxin-2调控神经元RNP凝聚体的运动和翻译，Aaxin-2多聚Q的扩张从根本上扰乱了mRNA的空间定位，并抑制了局部翻译。总体而言，这些结果表明，Aaxin-2多聚Q的扩展对转录本的稳定性、定位和翻译具有不利影响，这些转录本对轴突和细胞骨架的完整性至关重要，对运动神经元尤其重要。
Altered RNA metabolism is a common pathogenic mechanism linked to familial and sporadic Amyotrophic lateral sclerosis (ALS). ALS is characterized by mislocalization and aggregation of TDP-43, an RNA-binding protein (RBP) with multiple roles in post-transcriptional RNA processing. Recent studies have identified genetic interactions between TDP-43 and Ataxin-2, a polyglutamine (polyQ) RBP in which intermediate length polyQ expansions confer increased ALS risk. Here, we used live-cell confocal imaging, photobleaching and translation reporter assays to study the localization, transport dynamics and mRNA regulatory functions of TDP-43/Ataxin-2 in rodent primary cortical neurons. We show that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within ribonucleoprotein (RNP) condensates, and disrupt both its motility along the axon and liquid-like properties. Our data suggest that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, these results indicate Ataxin-2 polyQ expansions have detrimental effects on stability, localization, and translation of transcripts critical for axonal and cytoskeletal integrity, particularly important for motor neurons.