ArticleNeuron2024
Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes.
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Article in Neuron, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5citing papers in PubMed
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Who cites it
5 citing papers in PubMed.
- Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.bioRxiv : the preprint server for biology · 2026Article
- Article
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- The nuclear envelope and nuclear pore complexes in neurodegenerative diseases.Frontiers in cell and developmental biology · 2025Review
- CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.Acta neuropathologica communications · 2024Article
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Authors and funding
24 authors.
Norah Al-AzzamDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Neurosciences Graduate Program, University of California San Diego, San Diego, CA, USA.
Jenny H ToDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Vaishali GautamDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Lena A StreetDepartment of Biological Sciences, Columbia University, New York, NY, USA.
Chloe B NguyenDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Jack T NaritomiDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Dylan C LamDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Laboratories for Innovative Medicines, San Diego, CA, USA.
Assael A MadrigalDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Department of Biological Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
Benjamin LeeDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Wenhao JinSanford Laboratories for Innovative Medicines, San Diego, CA, USA.
Anthony AvinaDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Orel MizrahiDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Jasmine R MuellerDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Willard FordDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Cara R SchiavonDepartment of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA; Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Elena RebolloDepartment of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA; Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Anthony Q VuDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Steven M BlueDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Yashwin L MadakamutilDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Uri ManorDepartment of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA; Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Jeffrey D RothsteinBrain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Alyssa N CoyneBrain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Marko JovanovicDepartment of Biological Sciences, Columbia University, New York, NY, USA.
Gene W YeoDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Laboratories for Innovative Medicines, San Diego, CA, USA. Electronic address: geneyeo@ucsd.edu.
Funding
Viral Vector Core (VVC)P30CA014195 · NCI · SALK INSTITUTE FOR BIOLOGICAL STUDIES · PI Reuben Shaw · 1985 to 2026
$82.8MFunctional RNA elements in the human genomeR01HG004659 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Kevin Daniel Corbett, Eugene Wei-Ming Yeo · 2008 to 2026
$12.4MSan Diego Nathan Shock CenterP30AG068635 · NIA · SALK INSTITUTE FOR BIOLOGICAL STUDIES · PI SHADEL, GERALD · 2020 to 2024
$6.0MA comprehensive binding and functional map of human RNA-binding proteinsU24HG009889 · NHGRI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI GRAVELEY, BRENTON R., YEO, EUGENE WEI-MING · 2022 to 2025
$5.5MExtensive multiplexing of protein nucleic-acid interactions to comprehensively study gene expression regulation from chromatin to mRNA degradationR01HG012216 · NHGRI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI GUTTMAN, MITCHELL, JOVANOVIC, MARKO · 2022 to 2025
$3.1MDefining the programmed proteome rejuvenation underlying gametogenesisR01AG071869 · NIA · UNIVERSITY OF CALIFORNIA BERKELEY · PI BRAR, GLORIA ANN, JOVANOVIC, MARKO · 2021 to 2025
$2.9MRegulation of Protein Production Dynamics:RNA Binding Proteins and the Ribosome CodeR35GM128802 · NIGMS · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI JOVANOVIC, MARKO · 2018 to 2022
$2.3MNCI NIH HHS P30 CA014195NHGRI NIH HHS R01 HG004659NHGRI NIH HHS R01 HG012216NHGRI NIH HHS U24 HG009889NIA NIH HHS P30 AG068635NIA NIH HHS R01 AG071869NIGMS NIH HHS R35 GM128802
Abstract
Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.
Indexed as
Amyotrophic Lateral SclerosisDNA-Binding ProteinsInduced Pluripotent Stem CellsMotor NeuronsRNA-Binding ProteinsRNA SplicingActive Transport, Cell NucleusCell NucleusHumansPhenotypeDNA-Binding ProteinsRNA-Binding ProteinsTARDBP protein, humanALSamyotrophic lateral sclerosisCHMP7CRISPR screenneurodegenerationRNA splicingSmD1SMN complexTDP-43
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