Evidence map›Paper›PMID 34031600›Full record

ArticleNature neuroscience2021

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis.

Ruilin Tian, Anthony Abarientos, Jason Hong, Sayed Hadi Hashemi, Rui Yan, Nina Dräger, Kun Leng, Mike A Nalls, Andrew B Singleton, Ke Xu and 2 more

Open access · greenAbstract read
In one paragraph

Article in Nature neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 239 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
239citing papers in PubMed, 1 pooled it
31.2field-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

239 citing papers in PubMed, 1 synthesis or guideline pooled it, 395 citations in OpenAlex.

  1. Pooled it
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  15. Kat5 cKO mouse replicates biological domain signatures associated with Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
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  17. CoQExperimental & molecular medicine · 2026
    Review
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  20. Review

179 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 4 institutions in 2 countries.

Ruilin TianInstitute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. tianrl@sustech.edu.cn.ORCID http://orcid.org/0000-0001-7680-6682
Anthony AbarientosInstitute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Jason HongInstitute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Sayed Hadi HashemiDepartment of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Rui YanDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.ORCID http://orcid.org/0000-0003-3391-133X
Nina DrägerInstitute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Kun LengInstitute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-9931-1375
Mike A NallsLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Andrew B SingletonLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Ke XuDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.ORCID http://orcid.org/0000-0002-2788-194X
Faraz FaghriDepartment of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.ORCID http://orcid.org/0000-0001-5744-8728
Martin KampmannInstitute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. martin.kampmann@ucsf.edu.ORCID http://orcid.org/0000-0002-3819-7019
University of California, San Francisco · USNational Institutes of Health · USUniversity of California, Berkeley · USUniversity of Illinois Urbana-Champaign · US

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6M
Assessment of Candidate Loci in Neurological diseasesZIAAG000957 · NIA · NATIONAL INSTITUTE ON AGING · PI SINGLETON, ANDREW · 2009 to 2024
$12.2M
Project 3: Autophagy dysfunction and neuronal activity in FTDU54NS100717 · NINDS · WEILL MEDICAL COLL OF CORNELL UNIV · PI GAN, LI · 2016 to 2020
$10.8M
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSPR01AG060477 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Lea Tenenholz Grinberg, Thomas C Neylan · 2019 to 2026
$8.2M
Systematic elucidation of endosomal trafficking as a therapeutic opportunity in AD using CRISPR-based functional genomicsR01AG062359 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAMPMANN, MARTIN · 2018 to 2022
$3.2M
Intracellular phase separation at the nanoscale: a functional super-resolution approachDP2GM132681 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI XU, KE · 2018 to 2018
$2.4M
Rewiring of the human protein homeostasis network in normal and disease contextsDP2GM119139 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAMPMANN, MARTIN · 2015 to 2015
$2.3M
Assessment of Candidate Loci in Parkinson's diseaseZ01AG000957 · NIA · NATIONAL INSTITUTE ON AGING · PI SINGLETON, ANDREW B · 2003 to 2008
$1.2M
Uncovering mechanisms of selective vulnerability by CRISPR-based genetic screensR56AG057528 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRINBERG, LEA TENENHOLZ, KAMPMANN, MARTIN · 2018 to 2018
$769k
Elucidating cellular pathways controlling the reactive state of astrocytes in Alzheimer’s DiseaseF30AG066418 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LENG, KUN · 2019 to 2023
$155k
Intramural NIH HHS Z01 AG000957Intramural NIH HHS ZIA AG000957NIA NIH HHS F30 AG066418NIA NIH HHS R01 AG060477NIA NIH HHS R01 AG062359NIA NIH HHS R56 AG057528NIGMS NIH HHS DP2 GM119139NIGMS NIH HHS DP2 GM132681NIGMS NIH HHS T32 GM007618NINDS NIH HHS U54 NS100717
6 · The paper itself

Abstract

Single-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type-specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons. We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons after perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.

Indexed as

Clustered Regularly Interspaced Short Palindromic RepeatsFerroptosisGene Expression ProfilingHumansLysosomesNeuronsOxidative StressSaposinsPSAP protein, humanSaposins

Identifiers

PMID34031600
PMCPMC8254803
OpenAlexW3164329676

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.