Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. While pathogenic mutations in the DNA/RNA-binding protein Matrin-3 (MATR3) are linked to ALS and distal myopathy, the molecular mechanisms underlying MATR3-mediated neuromuscular degeneration remain unclear. We generated Drosophila lines with transgenic insertion of human MATR3 wildtype, disease-associated variants F115C and S85C, and deletion variants in functional domains, ΔRRM1, ΔRRM2, ΔZNF1 and ΔZNF2. We utilized genetic, behavioral and biochemical tools for comprehensive characterization of our models in vivo and in vitro. Additionally, we employed in silico approaches to find transcriptomic targets of MATR3 and hnRNPM from publicly available eCLIP datasets. We found that targeted expression of MATR3 in Drosophila muscles or motor neurons shorten lifespan and produces progressive motor defects, muscle degeneration and atrophy. Strikingly, deletion of its RNA-recognition motif (RRM2) mitigates MATR3 toxicity. We identified rump, the Drosophila homolog of human RNA-binding protein hnRNPM, as a modifier of mutant MATR3 toxicity in vivo. Interestingly, hnRNPM physically and functionally interacts with MATR3 in an RNA-dependent manner in mammalian cells. Furthermore, common RNA targets of MATR3 and hnRNPM converge in biological processes important for neuronal health and survival. We propose a model of MATR3-mediated neuromuscular degeneration governed by its RNA-binding domains and modulated by interaction with splicing factor hnRNPM.

中文翻译：

---

Matrin-3中的RNA识别基序通过与hnRNPM相互作用介导神经变性。

肌萎缩性侧索硬化症（ALS）是一种成人发作的致命性神经退行性疾病，其特征是上，下运动神经元的逐渐丧失。虽然DNA / RNA结合蛋白Matrin-3（MATR3）中的致病性突变与ALS和远端肌病有关，但MATR3介导的神经肌肉变性的分子机制仍不清楚。我们生成的果蝇系具有人类MATR3野生型的转基因插入，疾病相关变体F115C和S85C，以及功能域中的缺失变体ΔRRM1，ΔRRM2，ΔZNF1和ΔZNF2。我们利用遗传，行为和生化工具对我们的体内和体外模型进行了全面表征。此外，我们采用计算机方法从公开的eCLIP数据集中找到了MATR3和hnRNPM的转录组靶标。我们发现果蝇肌肉或运动神经元中MATR3的靶向表达会缩短寿命，并产生进行性运动缺陷，肌肉变性和萎缩。令人惊讶的是，删除其RNA识别基序（RRM2）可减轻MATR3的毒性。我们确定了臀部，人RNA结合蛋白hnRNPM的果蝇同源物，作为体内突变MATR3毒性的修饰剂。有趣的是，hnRNPM在哺乳动物细胞中以RNA依赖性的方式与MATR3发生物理和功能相互作用。此外，MATR3和hnRNPM的常见RNA靶点在对神经元健康和生存至关重要的生物学过程中会聚。我们提出了由其RNA结合域控制并与剪接因子hnRNPM相互作用调节的MATR3介导的神经肌肉变性模型。