ArticleNature medicine2018
Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.
2 registry-linked trialsOpen access · greenAbstract read
In one paragraph
Article in Nature medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 385 papers.
0numbers the graph read from it
0cells of the map it votes in
385citing papers in PubMed
51.2field-weighted citation impact, top 1% of its field
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.
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.
A Phase 1b, Open-Label, Multiple Ascending Dose, Multicenter Study of VRG50635 in Participants With Sporadic and Familial Amyotrophic Lateral Sclerosis Followed by Long-Term Treatment
A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of VRG50635 in Healthy Volunteers
Who cites it
385 citing papers in PubMed, 578 citations in OpenAlex.
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- PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
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- Target identification and assessment in the era of AI.Nature reviews. Drug discovery · 2026Review
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- A microphysiological system for screening lipid nanoparticle-mRNA complexes predicts in vivo heart transfection efficacy.Nature biomedical engineering · 2026Article
- Global transcriptional changes across multiple isogeniciScience · 2026Article
- Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Intrathecal (GActa neuropathologica communications · 2026Article
- Single-cell polygenic risk scores dissect cellular and molecular heterogeneity of complex human diseases.Nature biotechnology · 2026Article
- Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.bioRxiv : the preprint server for biology · 2026Article
- Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.Nucleic acids research · 2026Article
- Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.Genes · 2026Review
- Integrative genomic and functional analyses reveal NINL as a modulator of tau aggregation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration inInternational journal of molecular sciences · 2026Article
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325 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
43 authors at 6 institutions in 2 countries.
Yingxiao ShiDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Shaoyu LinDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Kim A StaatsDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.ORCID 0000-0001-8392-7992
Yichen LiDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Wen-Hsuan ChangDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Shu-Ting HungDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Eric HendricksDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Gabriel R LinaresDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Yaoming WangZilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Esther Y SonDepartment of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Xinmei WenJefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Kassandra KislerZilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Brent WilkinsonZilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Louise MenendezDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Tohru SugawaraDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Phillip WoolwineDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Mickey HuangDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Michael J CowanDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Brandon GeDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Nicole KoutsodendrisDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Kaitlin P SandorDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Jacob KombergDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Vamshidhar R VangoorDepartment of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Ketharini SenthilkumarDepartment of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Valerie HennesDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Carina SeahDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Amy R NelsonZilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Tze-Yuan ChengDRVision Technologies, LLC, Bellvue, Washington, USA.
Shih-Jong J LeeDRVision Technologies, LLC, Bellvue, Washington, USA.
Paul R AugustIcagen Corporation, Oro Valley, Arizona, USA.
Jason A ChenVerge Genomics, San Francisco, California, USA.
Nicholas WisniewskiVerge Genomics, San Francisco, California, USA.
Victor Hanson-SmithVerge Genomics, San Francisco, California, USA.
T Grant BelgardVerge Genomics, San Francisco, California, USA.ORCID 0000-0002-6962-7894
Alice ZhangVerge Genomics, San Francisco, California, USA.
Marcelo CobaZilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Chris GrunseichNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Michael E WardNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Leonard H van den BergDepartment of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
R Jeroen PasterkampDepartment of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.ORCID 0000-0003-1631-6440
Davide TrottiJefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Berislav V ZlokovicZilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.ORCID 0000-0002-6802-8232
Justin K IchidaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
University of Southern California · USUniversity Medical Center Utrecht · NLDRVision Technologies (United States) · USNational Institutes of Health · USThomas Jefferson University · USStanford University · US
Funding
VASCULAR RISK AND COGNITIVE STATUS IN A LATINO POPULATIONP50AG005142 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ARANDA, MARIA P. · 1985 to 2019
$41.0MUCLA-Caltech Medical Scientist Training ProgramT32GM008042 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI AJIJOLA, OLUJIMI A, DAWSON, DAVID WAYNE · 1985 to 2023
$29.9MVascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's DiseaseP01AG052350 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Daniel A Nation, ARTHUR W TOGA · 2016 to 2026
$28.4MStudies of Hereditary Neurological Disease: Disease MechanismsZIANS003038 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI FISCHBECK, KENNETH · 2009 to 2023
$19.5MAlzheimer's Abeta, Tau, Apolipoproteins and Blood-brain barrierR01NS034467 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI YASSINE, HUSSEIN N · 1995 to 2024
$9.1MValidating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTDR01NS097850 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA · 2016 to 2024
$5.5MTraining in Hearing & Communication NeuroscienceT32DC009975 · NIDCD · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Christopher A Shera · 2009 to 2026
$5.0MCerebrovascular beta-Amyloidosis: A-beta CNS Transport PathwaysR37AG023084 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZLOKOVIC, BERISLAV V · 2004 to 2013
$4.6MThe role of pericytes in the aging brain and pathogenesis and treatment of neurodegeneration, and Alzheimer's A-beta and tau pathologyRF1AG039452 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA · 2019 to 2019
$4.0MAlzheimer's Abeta, apolipoproteins and blood-brain barrierR37NS034467 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZLOKOVIC, BERISLAV V · 2007 to 2013
$3.4MLineage reprogramming for hearing loss: development of drug screening and gene therapy approachesR01DC015530 · NIDCD · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA, MCMAHON, ANDREW P. · 2016 to 2020
$3.0MCerebrovascular beta-Amyloidosis: A-beta CNS Transport PathwaysR01AG023084 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZLOKOVIC, BERISLAV V · 2015 to 2019
$3.0MNIA NIH HHS P01 AG052350NIA NIH HHS P50 AG005142NIA NIH HHS R01 AG023084NIA NIH HHS R01 AG039452NIA NIH HHS R37 AG023084NIA NIH HHS RF1 AG039452NIDCD NIH HHS R01 DC015530NIDCD NIH HHS T32 DC009975NINDS NIH HHS K99 NS077435NINDS NIH HHS R00 NS077435NINDS NIH HHS R01 NS034467NINDS NIH HHS R01 NS097850NINDS NIH HHS R21 NS090912NINDS NIH HHS R37 NS034467
Abstract
An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.
Indexed as
Amyotrophic Lateral SclerosisAnimalsC9orf72 ProteinDisease Models, AnimalDNA Repeat ExpansionEndosomesFrontotemporal DementiaGene Expression RegulationHaploinsufficiencyHumansIntronsMotor NeuronsMutationNerve Degenerationrab5 GTP-Binding ProteinsC9orf72 Proteinrab5 GTP-Binding Proteins
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Read underepoch 390
Registered trials
NCT06215755ClinicalTrials.gov
NCT06286475ClinicalTrials.gov
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.