Evidence map›Paper›PMID 34314701›Full record

ArticleCell2021

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

Kathryn R Bowles, M Catarina Silva, Kristen Whitney, Taylor Bertucci, Joshua E Berlind, Jesse D Lai, Jacob C Garza, Nathan C Boles, Sidhartha Mahali, Kevin H Strang and 15 more

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

Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
106citing papers in PubMed, 4 pooled it
9.4field-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

106 citing papers in PubMed, 4 syntheses or guidelines pooled it, 152 citations in OpenAlex.

  1. Pooled it
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  10. Human iPSC models revealResearch square · 2026
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46 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors at 7 institutions in 1 country.

Kathryn R BowlesRonald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA.
M Catarina SilvaChemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Kristen WhitneyRonald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA; Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA.
Taylor BertucciNeural Stem Cell Institute, Rensselaer, NY 12144, USA.
Joshua E BerlindDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Jesse D LaiDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Amgen Research, One Amgen Center Dr., Thousand Oaks, CA 91320, USA.
Jacob C GarzaChemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Nathan C BolesNeural Stem Cell Institute, Rensselaer, NY 12144, USA.
Sidhartha MahaliDepartment of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
Kevin H StrangRonald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA; Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA.
Jacob A MarshDepartment of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
Cynthia ChenDepartment of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
Derian A PughRonald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA.
Yiyuan LiuRonald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA.
Ronald E GordonDepartment of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA.
Susan K GoderieNeural Stem Cell Institute, Rensselaer, NY 12144, USA.
Rebecca ChowdhuryNeural Stem Cell Institute, Rensselaer, NY 12144, USA.
Steven LotzNeural Stem Cell Institute, Rensselaer, NY 12144, USA.
Keith LaneNeural Stem Cell Institute, Rensselaer, NY 12144, USA.
John F CraryDepartment of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA.
Stephen J HaggartyChemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Celeste M KarchDepartment of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
Justin K IchidaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Alison M GoateRonald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA. Electronic address: alison.goate@mssm.edu.
Sally TempleNeural Stem Cell Institute, Rensselaer, NY 12144, USA. Electronic address: sallytemple@neuralsci.org.
Neural Stem Cell Institute · USIcahn School of Medicine at Mount Sinai · USWashington University in St. Louis · USUniversity of Southern California · USAllen Institute for Brain Science · USHarvard University · USMassachusetts General Hospital · US

Funding

WASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI FAGAN, ANNE · 1985 to 2019
$52.1M
Research Education ComponentP30AG066444 · NIA · WASHINGTON UNIVERSITY · PI RICHARD Justin PERRIN · 2020 to 2026
$28.7M
Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)U01AG045390 · NIA · MAYO CLINIC ROCHESTER · PI BOEVE, BRADLEY F, ROSEN, HOWARD J · 2014 to 2018
$16.9M
Training - The Frontotemporal Lobar Degeneration Clinical Research ConsortiumU54NS092089 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BOXER, ADAM L. · 2014 to 2018
$6.4M
Validating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTDR01NS097850 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA · 2016 to 2024
$5.5M
Defining Characteristics of Cortical Progenitor Cells over Time in Mouse and HumanR35NS097277 · NINDS · REGENERATIVE RESEARCH FOUNDATION · PI TEMPLE, SALLY · 2017 to 2024
$5.0M
Regulation of tau expression in Alzheimer disease and agingR01AG054008 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI CRARY, JOHN FONDA · 2016 to 2020
$4.0M
Mechanisms of Age-Related TauopathyR01NS095252 · NINDS · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI John Fonda Crary · 2015 to 2026
$3.4M
iPSC Modeling of AD Using ProgerinR01AG056293 · NIA · REGENERATIVE RESEARCH FOUNDATION · PI TEMPLE, SALLY · 2017 to 2021
$2.5M
Big Omics Data Engine 2 SupercomputerS10OD026880 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KOVATCH, PATRICIA · 2019 to 2019
$2.0M
Targeting Tau Proteoforms in Frontotemporal DementiaRF1NS110890 · NINDS · WASHINGTON UNIVERSITY · PI KARCH, CELESTE MARIE · 2021 to 2021
$1.8M
Targeting Tau Proteoforms in Frontotemporal DementiaR01NS110890 · NINDS · WASHINGTON UNIVERSITY · PI KARCH, CELESTE MARIE · 2024 to 2024
$575k
NIA NIH HHS K01 AG046374NIA NIH HHS P30 AG066444NIA NIH HHS P50 AG005681NIA NIH HHS R01 AG054008NIA NIH HHS R01 AG056293NIA NIH HHS U01 AG045390NIH HHS S10 OD026880NINDS NIH HHS F31 NS117075NINDS NIH HHS R01 NS095252NINDS NIH HHS R01 NS097850NINDS NIH HHS R01 NS110890NINDS NIH HHS R35 NS097277NINDS NIH HHS R56 NS110890NINDS NIH HHS RF1 NS110890NINDS NIH HHS U54 NS092089
6 · The paper itself

Abstract

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

Indexed as

AutophagyBiomarkersBody PatterningCell DeathCell LineCerebrumELAV-Like Protein 4Glutamic AcidHumansHydrazonesLysosomesMorpholinesMutationNeuronsOrganoidsPhosphorylationapilimodBiomarkersELAV-Like Protein 4Glutamic AcidHydrazonesMAPT protein, humanMorpholinesPyrimidinestau ProteinsautophagyELAVL4frontotemporal dementiaglutamatergic neuronsMAPTorganoidssplicingsynaptic signalingtauopathy

Identifiers

PMID34314701
PMCPMC8635409
OpenAlexW3183726003

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

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.