Evidence map›Paper›PMID 38424324›Full record

ArticleNature neuroscience2024

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.

Carmelo Milioto, Mireia Carcolé, Ashling Giblin, Rachel Coneys, Olivia Attrebi, Mhoriam Ahmed, Samuel S Harris, Byung Il Lee, Mengke Yang, Robert A Ellingford and 30 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature neuroscience, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
12.6field-weighted citation impact, top 1% of its field
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

27 citing papers in PubMed, 34 citations in OpenAlex.

  1. Article
  2. RAN Translation-Coupled Decay of theInternational journal of molecular sciences · 2026
    Article
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  8. Review
  9. Article
  10. Article
  11. Article
  12. Article
  13. Brain communications · 2026
    Article
  14. Extracellular Matrix Remodeling in Motor Neuron Diseases.International journal of molecular sciences · 2025
    Review
  15. Article
  16. Article
  17. Challenges of modelling TDP-43 pathology in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2025
    Review
  18. Review
  19. Article
  20. Article
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

40 authors at 10 institutions in 4 countries.

Carmelo MiliotoUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0002-3844-0728
Mireia CarcoléUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0001-5054-9016
Ashling GiblinUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0001-8470-7908
Rachel ConeysUK Dementia Research Institute, University College London, London, UK.
Olivia AttrebiUK Dementia Research Institute, University College London, London, UK.
Mhoriam AhmedDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Samuel S HarrisUK Dementia Research Institute, University College London, London, UK.
Byung Il LeeUK Dementia Research Institute, University College London, London, UK.
Mengke YangUK Dementia Research Institute, University College London, London, UK.
Robert A EllingfordUK Dementia Research Institute, University College London, London, UK.
Raja S NirujogiAligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Daniel BiggsWellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Sally SalomonssonUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0001-6717-3369
Matteo ZanovelloDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Paula de OliveiraUK Dementia Research Institute, University College London, London, UK.
Eszter KatonaUK Dementia Research Institute, University College London, London, UK.
Idoia GlariaUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0003-4556-489X
Alla MikheenkoUK Dementia Research Institute, University College London, London, UK.
Bethany GearyAligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Evan UdineDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Deniz VaizogluUK Dementia Research Institute, University College London, London, UK.
Sharifah AnoarUCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
Khrisha JotangiyaUK Dementia Research Institute, University College London, London, UK.
Gerard CrowleyUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0003-0436-1332
Demelza M SmeethUK Dementia Research Institute, University College London, London, UK.
Mirjam L AdamsUK Dementia Research Institute, University College London, London, UK.
Teresa NiccoliUCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
Rosa RademakersVIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.ORCID http://orcid.org/0000-0002-4049-0863
Marka van BlitterswijkDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Anny DevoyUK Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.ORCID http://orcid.org/0000-0002-1293-0630
Soyon HongUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0002-5744-4871
Linda PartridgeUCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
Alyssa N CoyneDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-3658-5325
Pietro FrattaDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.ORCID http://orcid.org/0000-0002-8762-8188
Dario R AlessiAligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.ORCID http://orcid.org/0000-0002-2140-9185
Ben DaviesWellcome Centre for Human Genetics, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-3623-600X
Marc Aurel BuscheUK Dementia Research Institute, University College London, London, UK.ORCID http://orcid.org/0000-0002-4416-7553
Linda GreensmithDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Elizabeth M C FisherDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. elizabeth.fisher@ucl.ac.uk.ORCID http://orcid.org/0000-0003-2850-9936
Adrian M IsaacsUK Dementia Research Institute, University College London, London, UK. a.isaacs@ucl.ac.uk.ORCID http://orcid.org/0000-0002-6820-5534
UK Dementia Research Institute · GBNational Hospital for Neurology and Neurosurgery · GBMRC Unit for Lifelong Health and Ageing · GBUniversity of Dundee · GBCentre for Human Genetics · GBMayo Clinic in Florida · USQueen Mary University of London · GBJohns Hopkins University · USKing's College London · GBUniversity of Antwerp · BE

Funding

Medical Research Council G0601056Medical Research Council G0801110Medical Research Council MC_EX_MR/N501931/1Medical Research Council MR/S006508/1Medical Research Council MR/S017003/1Medical Research Council MR/V003585/1
6 · The paper itself

Abstract

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

Indexed as

Amyotrophic Lateral SclerosisFrontotemporal DementiaInduced Pluripotent Stem CellsAnimalsC9orf72 ProteinDipeptidesDNA Repeat ExpansionDrosophilaExtracellular MatrixHumansMiceMotor NeuronsTransforming Growth Factor beta1C9orf72 ProteinC9orf72 protein, humanDipeptidesTransforming Growth Factor beta1

Identifiers

PMID38424324
PMCPMC11001582
OpenAlexW4392294420

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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.