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

Zhe Zhang¹, Xiujuan Fu¹, Noelle Wright², Weiren Wang³, Yingzhi Ye², Julie Asbury⁴, Yini Li¹, Chengzhang Zhu⁵, Rong Wu¹, Shaopeng Wang¹, Shuying Sun⁶

Affiliations

¹ Department 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.
² Department 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.
³ Department 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.
⁴ Department 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.
⁵ Department 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.
⁶ Department 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.

PMID: 40073860
PMCID: PMC12005967 (available on 2026-04-16)
DOI: 10.1016/j.neuron.2025.02.005

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

Zhe Zhang et al. Neuron. 2025.

. 2025 Apr 16;113(8):1190-1205.e9.

doi: 10.1016/j.neuron.2025.02.005. Epub 2025 Mar 11.

Authors

Zhe Zhang¹, Xiujuan Fu¹, Noelle Wright², Weiren Wang³, Yingzhi Ye², Julie Asbury⁴, Yini Li¹, Chengzhang Zhu⁵, Rong Wu¹, Shaopeng Wang¹, Shuying Sun⁶

Affiliations

¹ Department 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.
² Department 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.
³ Department 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.
⁴ Department 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.
⁵ Department 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.
⁶ Department 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.

PMID: 40073860
PMCID: PMC12005967 (available on 2026-04-16)
DOI: 10.1016/j.neuron.2025.02.005

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.

Keywords: ALS; C9ORF72; CRISPR screening; FTD; PI3P; PTPσ; endosome; lysosome; poly-GR/PR.

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Conflict of interest statement

Declaration of interests S.S. and Z.Z. are inventors on a patent application (PCT/US2024/027681) related to research presented in this study.

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

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

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