Evidence map›Paper›PMID 42087256›Full record

ArticleActa neuropathologica communications2026

Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.

Nikki S Harper, Joanne L Sharpe, Jasmine Speranza, Ravinder Gulia, Jeffrey X Chen, Scott P Allen, Manpreet S Atwal, Stuart Pickering-Brown, Matthew R Livesey, Craig L Bennett and 3 more

Abstract read
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In one paragraph

Article in Acta neuropathologica communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

13 authors.

Nikki S HarperDivision of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Joanne L Sharpe *Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Jasmine Speranza *Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Ravinder GuliaDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, 92617, USA.
Jeffrey X ChenDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, 92617, USA.
Scott P AllenSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Manpreet S AtwalSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Stuart Pickering-BrownDivision of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Matthew R LiveseySheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Craig L BennettDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, 92617, USA.
Andreas ProkopDivision of Molecular and Cellular Function, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
Albert R La SpadaDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, 92617, USA.
Ryan J H WestSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK. r.j.west@sheffield.ac.uk.

Funding

Resource Component: Acquisition, maintenance and distribution of Drosophila stocksP40OD018537 · OD · TRUSTEES OF INDIANA UNIVERSITY · PI Annette L. Parks · 2014 to 2026
$13.5M
La Spada Outstanding Investigator AwardR35NS122140 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI ALBERT R LA SPADA · 2021 to 2026
$7.2M
Alzheimer's Society 510Alzheimer's Society and The Heather Corrie Impact Fund 630Motor Neurone Disease Association Livesey/Oct20/900-792National Institutes of Health (NIH) NIH R35 NS122140NIH HHS P40 OD018537NINDS NIH HHS R35 NS122140Wellcome Trust 087742/Z/08/Z
6 · The paper itself

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2α phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2α phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.

Indexed as

Amyotrophic Lateral SclerosisAtaxin-2C9orf72 ProteinFrontotemporal DementiaAnimalsAnimals, Genetically ModifiedDisease Models, AnimalDNA Repeat ExpansionDrosophilaDrosophila ProteinsHumansIntegrated Stress ResponseStress GranulesAtaxin-2ATX2 protein, DrosophilaC9orf72 ProteinC9orf72 protein, humanDrosophila ProteinsAmyotrophic lateral sclerosisAtaxin-2C9orf72DrosophilaFrontotemporal dementiaIntegrated stress responseMotor neurone diseaseStress granules

Identifiers

PMID42087256
PMCPMC13251143

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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.