DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay

  • Neuron. 2026 Jun 3;114(11):1970-1985.e12. doi: 10.1016/j.neuron.2026.01.018.
Yingzhi Ye  1 ,  Zhe Zhang  2 ,  Yu Xiao  3 ,  Chengzhang Zhu  4 ,  Noelle Wright  1 ,  Julie Asbury  2 ,  Yongxin Huang  1 ,  Weiren Wang  2 ,  Laura Gomez-Isaza  5 ,  Juan C Troncoso  5 ,  Chuan He  6 ,  Shuying Sun  7
Affiliations
  • 1. Department of Physiology, Pharmacology & Therapeutics, 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.
  • 2. Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 3. Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA.
  • 4. Department of Physiology, Pharmacology & Therapeutics, 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.
  • 5. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 6. Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
  • 7. Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: [email protected].
PMID: 41943580 DOI: 10.1016/j.neuron.2026.01.018
Abstract

The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping scavenger enzyme (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation via dysregulating the properties and activity of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Loss of TDP-43 hyperactivates P-bodies, increasing mRNA association and RNA decay. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.

Keywords
ALS; DCPS; FTD; P-body; RNA decay; TDP-43; neurodegeneration.
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