Evidence map›Paper›PMID 39181135›Full record

ArticleNeuron2024

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 and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuron, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
  4. RAN Translation-Coupled Decay of theInternational journal of molecular sciences · 2026
    Article
  5. Article
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  7. Article
  8. Review
  9. Article
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  12. Article
  13. Review
  14. Article
  15. Multiple sclerosis: molecular pathogenesis and therapeutic intervention.Signal transduction and targeted therapy · 2025
    Review
  16. Article
  17. Article
  18. SON-dependent nuclear speckle rehabilitation alleviates proteinopathies.bioRxiv : the preprint server for biology · 2025
    Article
  19. Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.bioRxiv : the preprint server for biology · 2025
    Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Rong WuDepartment 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.
Yingzhi YeDepartment 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.
Daoyuan DongDepartment 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.
Zhe ZhangDepartment 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.
Shaopeng WangDepartment 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.
Yini LiDepartment 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.
Noelle WrightDepartment 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.
Javier Redding-OchoaDepartment 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.
Koping ChangDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shaohai XuSchool of Biological Sciences, Nanyang Technological University, 637551 Singapore, Singapore.
Xueting TuDepartment 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.
Chengzhang ZhuDepartment 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.
Lyle W OstrowDepartment of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19122, USA.
Xavier RocaSchool of Biological Sciences, Nanyang Technological University, 637551 Singapore, Singapore.
Juan C TroncosoDepartment 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.
Bin WuDepartment 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.
Shuying SunDepartment 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: shuying.sun@jhmi.edu.

Funding

Research Education ComponentP30AG066507 · NIA · JOHNS HOPKINS UNIVERSITY · PI MARILYN S. ALBERT · 2020 to 2026
$29.3M
Single molecule study of C9ORF72 repeat RNA metabolisms in ALS/FTDRF1NS113820 · NINDS · JOHNS HOPKINS UNIVERSITY · PI SUN, SHUYING, WU, BIN · 2020 to 2025
$6.2M
Regulation mechanism and functional genomics of LINE1 RNA in TDP-43 linked neurodegenerationR01AG078948 · NIA · JOHNS HOPKINS UNIVERSITY · PI Xianjun Dong, Shuying Sun · 2022 to 2026
$4.2M
The role of m6A RNA methylation in C9ORF72-ALS/FTDRF1NS127925 · NINDS · JOHNS HOPKINS UNIVERSITY · PI SUN, SHUYING · 2022 to 2024
$2.0M
Molecular mechanism of dipeptide repeat protein production from hexanucleotide repeats in C9ORF72-related ALS and FTDR01NS107347 · NINDS · JOHNS HOPKINS UNIVERSITY · PI SUN, SHUYING · 2018 to 2022
$1.8M
The role of m6A RNA methylation in C9ORF72-ALS/FTDR01NS127925 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Shuying Sun · 2025 to 2026
$1.2M
NIA NIH HHS P30 AG066507NIA NIH HHS R01 AG078948NINDS NIH HHS R01 NS107347NINDS NIH HHS R01 NS127925NINDS NIH HHS RF1 NS113820NINDS NIH HHS RF1 NS127925
6 · The paper itself

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.

Indexed as

Amyotrophic Lateral SclerosisC9orf72 ProteinFrontotemporal DementiaRNA-Binding ProteinsRNA SplicingAnimalsDNA Repeat ExpansionFemaleHumansInduced Pluripotent Stem CellsMaleMiceNeuronsC9orf72 ProteinC9orf72 protein, humanRNA-Binding ProteinsSRRM2 protein, humanALSC9ORF72FTDneurodegenerationnuclear specklerepeat expansionRNA splicingSRRM2

Identifiers

PMID39181135
PMCPMC11502262

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.