Evidence map›Paper›PMID 25535386›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2015

Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease.

Reut Shema, Ruth Kulicke, Glenn S Cowley, Rachael Stein, David E Root, Myriam Heiman

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

Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
0.7field-weighted citation impact, top 35% 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

22 citing papers in PubMed, 40 citations in OpenAlex.

  1. Review
  2. Review
  3. GPx6 downregulation drives ferroptosis in Kashin-Beck disease chondrocytes via the SLC7A11/GPx4 axis.Apoptosis : an international journal on programmed cell death · 2026
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  18. Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019
    Review
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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

6 authors at 3 institutions in 1 country.

Reut ShemaThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
Ruth KulickeThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
Glenn S CowleyThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142;
Rachael SteinThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
David E RootThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142;
Myriam HeimanThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 mheiman@MIT.edu.
Broad Institute · USHarvard University · USMassachusetts Institute of Technology · US

Funding

Development of SLIC, a methodology for synthetic lethal screening in the CNSR01NS085880 · NINDS · BROAD INSTITUTE, INC. · PI HEIMAN, MYRIAM · 2013 to 2016
$1.4M
NINDS NIH HHS R01 NS085880NINDS NIH HHS R01NS085880
6 · The paper itself

Abstract

Huntington's disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical and striatal neurons, as well as morbidity in midlife. Human genetic studies led to the identification of the causative gene, huntingtin. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death. However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has complicated efforts to understand the etiology of this disease, and to date no curative therapeutic exists. To address the general problem of identifying the disease-phenotype contributing genes from a large number of correlative studies, here we develop a synthetic lethal screening methodology for the mammalian central nervous system, called SLIC, for synthetic lethal in the central nervous system. Applying SLIC to the study of Huntington's disease, we identify the age-regulated glutathione peroxidase 6 (Gpx6) gene as a modulator of mutant huntingtin toxicity and show that overexpression of Gpx6 can dramatically alleviate both behavioral and molecular phenotypes associated with a mouse model of Huntington's disease. SLIC can, in principle, be used in the study of any neurodegenerative disease for which a mouse model exists, promising to reveal modulators of neurodegenerative disease in an unbiased fashion, akin to screens in simpler model organisms.

Indexed as

AnimalsBehavior, AnimalCentral Nervous SystemDisease Models, AnimalGene Expression RegulationGlutathione PeroxidaseHumansHuntington DiseaseMiceMotor ActivityNeostriatumGlutathione PeroxidaseGpx6 protein, mouseglutathione peroxidaseHuntington’s diseasepooled screeningstriatumsynthetic lethality

Identifiers

PMID25535386
PMCPMC4291668
OpenAlexW2131539955

What OpenQuestion holds

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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.