Evidence map›Paper›PMID 33482083›Full record

ArticleCell2021

p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

Maya Maor-Nof, Zohar Shipony, Rodrigo Lopez-Gonzalez, Lisa Nakayama, Yong-Jie Zhang, Julien Couthouis, Jacob A Blum, Patricia A Castruita, Gabriel R Linares, Kai Ruan and 17 more

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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 116 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
116citing papers in PubMed, 2 pooled it
14.3field-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

116 citing papers in PubMed, 2 syntheses or guidelines pooled it, 166 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Article
  4. G-Quadruplexes: Structural Diversity and Emerging Roles in Biomolecular Condensation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Review
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56 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 8 institutions in 1 country.

Maya Maor-NofDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: maormaya@stanford.edu.
Zohar ShiponyDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Rodrigo Lopez-GonzalezDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Lisa NakayamaDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Yong-Jie ZhangDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Julien CouthouisDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Jacob A BlumDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Patricia A CastruitaMemory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Gabriel R LinaresDepartment of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA.
Kai RuanDepartment of Neurology, Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Gokul RamaswamiDepartment of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
David J SimonDepartment of Biology, Stanford University, Stanford, CA, USA.
Aviv NofDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Manuel SantanaDepartment of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA.
Kyuho HanDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Nasa Sinnott-ArmstrongDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Michael C BassikDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Daniel H GeschwindDepartment of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Marc Tessier-LavigneDepartment of Biology, Stanford University, Stanford, CA, USA.
Laura D AttardiDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
Thomas E LloydDepartment of Neurology, Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Justin K IchidaDepartment of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA.
Fen-Biao GaoDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
William J GreenleafDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Jennifer S YokoyamaMemory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Aaron D GitlerDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: agitler@stanford.edu.
Stanford University · USUniversity of Southern California · USJohns Hopkins University · USMayo Clinic in Florida · USUniversity of California, Los Angeles · USUniversity of California, San Francisco · USUniversity of Massachusetts Chan Medical School · USStanford Medicine · US

Funding

VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGEDU19AI057266 · NIAID · EMORY UNIVERSITY · PI Rafi Ahmed · 2003 to 2026
$81.7M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
PRODUCTION CENTER FOR MAPPING REGULATORY REGIONS OF THE HUMAN GENOMEUM1HG009442 · NHGRI · STANFORD UNIVERSITY · PI SNYDER, MICHAEL P. · 2017 to 2021
$20.1M
Project 3: Neuropathology of the multi-proteinopathy of c9FTD/ALS.P01NS084974 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2014 to 2024
$17.6M
Special EquipmentP50HG007735 · NHGRI · STANFORD UNIVERSITY · PI CHANG, HOWARD Y · 2014 to 2018
$15.2M
Center for Personal Dynamic RegulomesRM1HG007735 · NHGRI · STANFORD UNIVERSITY · PI CHANG, HOWARD Y · 2019 to 2023
$13.8M
Integrative approaches to elucidate p53 transcriptional networks during carcinogenesisR35CA197591 · NCI · STANFORD UNIVERSITY · PI LAURA D ATTARDI · 2015 to 2026
$11.6M
Expanding insights into FTD disease mechanismsR35NS097273 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2017 to 2024
$10.6M
Innovating Yeast and Human Genetics Approaches to Define Mechanisms of Neurodegenerative DiseaseR35NS097263 · NINDS · STANFORD UNIVERSITY · PI GITLER, AARON D. · 2017 to 2024
$8.6M
Integration of genetic association mapping and functional data to elucidate genetic mechanisms of diseaseR01HG008140 · NHGRI · STANFORD UNIVERSITY · PI JONATHAN K PRITCHARD · 2016 to 2026
$7.3M
Validation of r(G4C2)exp-binding small molecules in vivo and c9FTD/ALS biomarker developmentP01NS099114 · NINDS · UNIVERSITY OF FLORIDA · PI DISNEY, MATTHEW D · 2017 to 2021
$6.5M
VECTOR COREP30NS069375 · NINDS · STANFORD UNIVERSITY · PI OLSON, ANDREW · 2011 to 2019
$6.3M
NCI NIH HHS R35 CA197591NHGRI NIH HHS P50 HG007735NHGRI NIH HHS R01 HG008140NHGRI NIH HHS RM1 HG007735NHGRI NIH HHS UM1 HG009436NHGRI NIH HHS UM1 HG009442NIAID NIH HHS U19 AI057266NIA NIH HHS K01 AG049152NIA NIH HHS P01 AG019724NIA NIH HHS R01 AG062588NIA NIH HHS RF1 AG064690NIDCD NIH HHS R01 DC015530NIDCD NIH HHS T32 DC009975NIH HHS S10 OD020141NIMH NIH HHS F32 MH114620NIMH NIH HHS R01 MH109912NINDS NIH HHS P01 NS084974NINDS NIH HHS P01 NS099114NINDS NIH HHS P30 NS069375NINDS NIH HHS R01 NS057553NINDS NIH HHS R01 NS089786NINDS NIH HHS R01 NS094239NINDS NIH HHS R01 NS097850NINDS NIH HHS R01 NS101986NINDS NIH HHS R35 NS097263NINDS NIH HHS R35 NS097273NINDS NIH HHS R37 NS057553NINDS NIH HHS RF1 NS101986
6 · The paper itself

Abstract

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.

Indexed as

AnimalsApoptosis Regulatory ProteinsAxonsC9orf72 ProteinCell DeathCells, CulturedCerebral CortexChromatinDisease Models, AnimalDNA DamageDNA Repeat ExpansionDrosophilaMiceMice, Inbred C57BLNerve DegenerationProtein StabilityApoptosis Regulatory ProteinsC9orf72 ProteinChromatinPUMA protein, mouseTumor Suppressor Protein p53Tumor Suppressor Proteinsamyotrophic lateral sclerosisATAC-seqaxonal degenerationC9orf72neurodegenerationp53pumaTDP-43

Identifiers

PMID33482083
PMCPMC7886018
OpenAlexW3126136328

What OpenQuestion holds

Textmetadata
LicenceTDM
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.