Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS,Neuron

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Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS
Neuron ( IF 14.7 ) Pub Date : 2024-08-23 , DOI: 10.1016/j.neuron.2024.07.025
Rong Wu ₁ , Yingzhi Ye ₂ , Daoyuan Dong ₁ , Zhe Zhang ₁ , Shaopeng Wang ₃ , Yini Li ₁ , Noelle Wright ₁ , Javier Redding-Ochoa ₄ , Koping Chang ₅ , Shaohai Xu ₆ , Xueting Tu ₁ , Chengzhang Zhu ₇ , Lyle W Ostrow ₈ , Xavier Roca ₆ , Juan C Troncoso ₄ , Bin Wu ₉ , Shuying Sun ₁₀

Affiliation

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Physiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
School of Biological Sciences, Nanyang Technological University, 637551 Singapore, Singapore.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19122, USA.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.

中文翻译：

核斑点完整性的破坏使 C9ORF72-FTD/ALS 中的 RNA 剪接失调

C9ORF72 基因内含子（GGGGCC）n 重复序列的扩增是额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）（C9-FTD/ALS）的最常见遗传原因，其特征是异常重复 RNA 病灶和非经典翻译产生的二肽重复序列（DPR）蛋白包涵体。在这里，我们阐明了（GGGGCC）n 重复 RNA 与核斑点共定位并改变它们的相分离特性和颗粒动力学。此外，必需的核斑点支架蛋白 SRRM2 被隔离在 C9-FTD/ALS 小鼠模型和患者死后组织的 poly-GR 细胞质包涵体中，加剧了核斑点功能障碍。核斑点完整性受损会诱导人类 iPSC 衍生神经元的全局外显子跳跃和内含子保留，并导致神经元毒性。在 C9-FTD/ALS 患者死后组织中可以发现类似的选择性剪接变化。这项工作确定了 C9-FTD/ALS 中核斑点功能受损导致整体 RNA 剪接缺陷的新分子机制，并揭示了新的潜在生物标志物或治疗靶点。

更新日期：2024-08-23

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