Evidence map›Paper›PMID 39593143›Full record

ArticleMolecular neurodegeneration2024

Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB.

Benjamin E Clarke, Oliver J Ziff, Giulia Tyzack, Marija Petrić Howe, Yiran Wang, Pierre Klein, Claudia A Smith, Cameron A Hall, Adel Helmy, Michael Howell and 2 more

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In one paragraph

Article in Molecular neurodegeneration, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing 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

8 citing papers in PubMed.

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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

12 authors.

Benjamin E Clarke *Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK. ben.clarke@crick.ac.uk.
Oliver J Ziff *Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK. oliver.ziff@crick.ac.uk.
Giulia TyzackDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
Marija Petrić HoweDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
Yiran WangDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
Pierre KleinDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
Claudia A SmithDivision of Neurosurgery and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Cameron A HallDivision of Neurosurgery and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Adel HelmyDivision of Neurosurgery and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Michael HowellThe Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Gavin KellyThe Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Rickie PataniDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK. rickie.patani@ucl.ac.uk.

Funding

Wellcome Trust
6 · The paper itself

Abstract

backgroundMicroglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.

methodsHere, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.

resultsTranscriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.

conclusionsVCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.

Indexed as

Amyotrophic Lateral SclerosisFrontotemporal DementiaInduced Pluripotent Stem CellsLysosomesMembrane GlycoproteinsMicrogliaValosin Containing ProteinAnimalsAstrocytesHumansMiceMotor NeuronsMutationPhenotypeGPNMB protein, humanMembrane GlycoproteinsValosin Containing ProteinVCP protein, human

Identifiers

PMID39593143
PMCPMC11590569

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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.