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

Rong Wu; Yingzhi Ye; Daoyuan Dong; Zhe Zhang; Shaopeng Wang; Yini Li; Noelle Wright; Javier Redding-Ochoa; Koping Chang; Shaohai Xu; Xueting Tu; Chengzhang Zhu; Lyle W Ostrow; Xavier Roca; Juan C Troncoso; Bin Wu; Shuying Sun

doi:10.1016/j.neuron.2024.07.025

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

Neuron. 2024 Oct 23;112(20):3434-3451.e11. doi: 10.1016/j.neuron.2024.07.025. Epub 2024 Aug 23.

Authors

Rong Wu¹, Yingzhi Ye², Daoyuan Dong¹, Zhe Zhang¹, Shaopeng Wang³, Yini Li¹, Noelle Wright¹, Javier Redding-Ochoa⁴, Koping Chang⁵, Shaohai Xu⁶, Xueting Tu¹, Chengzhang Zhu⁷, Lyle W Ostrow⁸, Xavier Roca⁶, Juan C Troncoso⁴, Bin Wu⁹, Shuying Sun¹⁰

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ School of Biological Sciences, Nanyang Technological University, 637551 Singapore, Singapore.
⁷ 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.
⁸ Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19122, USA.
⁹ 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.
¹⁰ 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. Electronic address: [email protected].

PMID: 39181135
PMCID: PMC11502262 (available on 2025-10-23)
DOI: 10.1016/j.neuron.2024.07.025

Abstract

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.

Keywords: ALS; C9ORF72; FTD; RNA splicing; SRRM2; neurodegeneration; nuclear speckle; repeat expansion.

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Animals
C9orf72 Protein* / genetics
C9orf72 Protein* / metabolism
DNA Repeat Expansion / genetics
Female
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / metabolism
Frontotemporal Dementia* / pathology
Humans
Induced Pluripotent Stem Cells / metabolism
Male
Mice
Neurons / metabolism
RNA Splicing* / genetics
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism

Substances

C9orf72 Protein
RNA-Binding Proteins
SRRM2 protein, human
C9orf72 protein, human

Abstract

MeSH terms

Substances

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