Evidence map›Paper›PMID 37736756›Full record

ArticleNature communications2023

C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.

Björn F Vahsen, Sumedha Nalluru, Georgia R Morgan, Lucy Farrimond, Emily Carroll, Yinyan Xu, Kaitlyn M L Cramb, Benazir Amein, Jakub Scaber, Antigoni Katsikoudi and 9 more

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

Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
56citing papers in PubMed, 1 pooled it
13.0field-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

56 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.

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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

19 authors at 5 institutions in 2 countries.

Björn F VahsenOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.ORCID http://orcid.org/0000-0002-5159-5070
Sumedha NalluruOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Georgia R MorganOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Lucy FarrimondOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Emily CarrollOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Yinyan XuOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Kaitlyn M L CrambKavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, OX1 3QU, UK.
Benazir AmeinOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.ORCID http://orcid.org/0009-0004-1314-3518
Jakub ScaberOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.ORCID http://orcid.org/0000-0003-0146-1821
Antigoni KatsikoudiKavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, OX1 3QU, UK.
Ana CandalijaOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Mireia CarcoléUK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WCIN 3BG, UK.ORCID http://orcid.org/0000-0001-5054-9016
Ruxandra DafincaOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.ORCID http://orcid.org/0000-0003-0776-6431
Adrian M IsaacsUK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WCIN 3BG, UK.ORCID http://orcid.org/0000-0002-6820-5534
Richard Wade-MartinsKavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, OX1 3QU, UK.ORCID http://orcid.org/0000-0001-6691-580X
Elizabeth GrayOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Martin R TurnerOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.ORCID http://orcid.org/0000-0003-0267-3180
Sally A CowleyJames and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. sally.cowley@path.ox.ac.uk.ORCID http://orcid.org/0000-0003-0297-6675
Kevin TalbotOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. kevin.talbot@ndcn.ox.ac.uk.ORCID http://orcid.org/0000-0001-5490-1697
John Radcliffe Hospital · GBUniversity of Oxford · GBUK Dementia Research Institute · GBChinese Academy of Medical Sciences & Peking Union Medical College · CNOxford Research Group · GB

Funding

Department of HealthMedical Research Council MR/M024962/1Medical Research Council MR/N013468/1Motor Neurone Disease Association TURNER/OCT18/989-797Motor Neurone Disease Association WADE-MARTINS/OCT13/867-792Wellcome Trust 102176/Z/13/ZWellcome Trust 203141/Z/16/Z
6 · The paper itself

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.

Indexed as

Amyotrophic Lateral SclerosisInduced Pluripotent Stem CellsNeurodegenerative DiseasesC9orf72 ProteinCoculture TechniquesHumansLipopolysaccharidesMatrix Metalloproteinase 9MicrogliaMotor NeuronsC9orf72 ProteinC9orf72 protein, humanLipopolysaccharidesMatrix Metalloproteinase 9MMP9 protein, human

Identifiers

PMID37736756
PMCPMC10517114
OpenAlexW4386945518

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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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.