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Remyelination protects neurons from DLK-mediated neurodegeneration

Author

Listed:
  • Greg J. Duncan

    (Oregon Health & Science University)

  • Sam D. Ingram

    (Oregon Health & Science University)

  • Katie Emberley

    (Oregon Health & Science University)

  • Jo Hill

    (Oregon Health & Science University)

  • Christian Cordano

    (University of California San Francisco
    University of Genoa
    IRCCS Ospedale Policlinico San Martino)

  • Ahmed Abdelhak

    (University of California San Francisco)

  • Michael McCane

    (Oregon Health & Science University)

  • Jennifer E. Jenks

    (Oregon Health & Science University)

  • Nora Jabassini

    (University of California San Francisco)

  • Kirtana Ananth

    (University of California San Francisco)

  • Skylar J. Ferrara

    (Oregon Health & Science University)

  • Brittany Stedelin

    (Oregon Health & Science University)

  • Benjamin Sivyer

    (Oregon Health & Science University)

  • Sue A. Aicher

    (Oregon Health & Science University)

  • Thomas S. Scanlan

    (Oregon Health & Science University)

  • Trent A. Watkins

    (University of California San Francisco)

  • Anusha Mishra

    (Oregon Health & Science University)

  • Jonathan W. Nelson

    (Oregon Health & Science University
    University of Southern California)

  • Ari J. Green

    (University of California San Francisco)

  • Ben Emery

    (Oregon Health & Science University)

Abstract

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.

Suggested Citation

  • Greg J. Duncan & Sam D. Ingram & Katie Emberley & Jo Hill & Christian Cordano & Ahmed Abdelhak & Michael McCane & Jennifer E. Jenks & Nora Jabassini & Kirtana Ananth & Skylar J. Ferrara & Brittany Ste, 2024. "Remyelination protects neurons from DLK-mediated neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53429-5
    DOI: 10.1038/s41467-024-53429-5
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    References listed on IDEAS

    as
    1. Xi Xiang & Giulia I. Corsi & Christian Anthon & Kunli Qu & Xiaoguang Pan & Xue Liang & Peng Han & Zhanying Dong & Lijun Liu & Jiayan Zhong & Tao Ma & Jinbao Wang & Xiuqing Zhang & Hui Jiang & Fengping, 2021. "Enhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Janos Groh & Tassnim Abdelwahab & Yogita Kattimani & Michaela Hörner & Silke Loserth & Viktoria Gudi & Robert Adalbert & Fabian Imdahl & Antoine-Emmanuel Saliba & Michael Coleman & Martin Stangel & Mi, 2023. "Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
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