Evidence map›Paper›PMID 40073860›Full record

ArticleNeuron2025

PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.

Zhe Zhang, Xiujuan Fu, Noelle Wright, Weiren Wang, Yingzhi Ye, Julie Asbury, Yini Li, Chengzhang Zhu, Rong Wu, Shaopeng Wang and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuron, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
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

11 authors.

Zhe ZhangDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Xiujuan FuDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Noelle WrightDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Physiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Weiren WangDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biotechology Master Program, Johns Hopkins University, Baltimore, MD 21205, USA.
Yingzhi YeDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Physiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Julie AsburyDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Notre Dame of Maryland University, Baltimore, MD 21210, USA.
Yini LiDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Chengzhang ZhuDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Rong WuDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shaopeng WangDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shuying SunDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: shuying.sun@jhmi.edu.

Funding

Single molecule study of C9ORF72 repeat RNA metabolisms in ALS/FTDRF1NS113820 · NINDS · JOHNS HOPKINS UNIVERSITY · PI SUN, SHUYING, WU, BIN · 2020 to 2025
$6.2M
Regulation mechanism and functional genomics of LINE1 RNA in TDP-43 linked neurodegenerationR01AG078948 · NIA · JOHNS HOPKINS UNIVERSITY · PI Xianjun Dong, Shuying Sun · 2022 to 2026
$4.2M
The role of m6A RNA methylation in C9ORF72-ALS/FTDRF1NS127925 · NINDS · JOHNS HOPKINS UNIVERSITY · PI SUN, SHUYING · 2022 to 2024
$2.0M
Dysregulation of inhibitory synapse by poly-GR in C9ORF72-ALS/FTDR21AG072078 · NIA · JOHNS HOPKINS UNIVERSITY · PI SUN, SHUYING · 2021 to 2021
$450k
NIA NIH HHS R01 AG078948NIA NIH HHS R21 AG072078NINDS NIH HHS RF1 NS113820NINDS NIH HHS RF1 NS127925
6 · The paper itself

Abstract

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.

Indexed as

Amyotrophic Lateral SclerosisC9orf72 ProteinFrontotemporal DementiaPhosphatidylinositol PhosphatesReceptor-Like Protein Tyrosine Phosphatases, Class 2AnimalsEndosomesHumansLysosomesMiceNeuronsC9orf72 ProteinC9orf72 protein, humanPhosphatidylinositol PhosphatesReceptor-Like Protein Tyrosine Phosphatases, Class 2ALSC9ORF72CRISPR screeningendosomeFTDlysosomePI3Ppoly-GR/PRPTPσ

Identifiers

PMID40073860
PMCPMC12005967

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.