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Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy

Author

Listed:
  • Amy-Jayne Hutchings

    (University Hospital Würzburg)

  • Bita Hambrecht

    (University Hospital Würzburg)

  • Alexander Veh

    (University Hospital Würzburg)

  • Neha Jadhav Giridhar

    (University Hospital Würzburg)

  • Abdolhossein Zare

    (University Hospital Würzburg)

  • Christina Angerer

    (University Hospital Würzburg)

  • Thorben Ohnesorge

    (University Hospital Würzburg)

  • Maren Schenke

    (University of Veterinary Medicine Hannover
    Johns Hopkins University)

  • Bhuvaneish T. Selvaraj

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Siddharthan Chandran

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Jared Sterneckert

    (Center for Regenerative Therapies TU Dresden
    Medical Faculty Carl Gustav Carus of TU Dresden)

  • Susanne Petri

    (Hannover Medical School)

  • Bettina Seeger

    (University of Veterinary Medicine Hannover)

  • Michael Briese

    (University Hospital Würzburg)

  • Christian Stigloher

    (University of Würzburg)

  • Thorsten Bischler

    (University of Würzburg)

  • Andreas Hermann

    (University Medical Center Rostock
    University Medical Center Rostock
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald)

  • Markus Damme

    (Christian-Albrechts-University Kiel)

  • Michael Sendtner

    (University Hospital Würzburg)

  • Patrick Lüningschrör

    (University Hospital Würzburg)

Abstract

Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.

Suggested Citation

  • Amy-Jayne Hutchings & Bita Hambrecht & Alexander Veh & Neha Jadhav Giridhar & Abdolhossein Zare & Christina Angerer & Thorben Ohnesorge & Maren Schenke & Bhuvaneish T. Selvaraj & Siddharthan Chandran , 2024. "Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52875-5
    DOI: 10.1038/s41467-024-52875-5
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    References listed on IDEAS

    as
    1. Patrick Lüningschrör & Beyenech Binotti & Benjamin Dombert & Peter Heimann & Angel Perez-Lara & Carsten Slotta & Nadine Thau-Habermann & Cora R. von Collenberg & Franziska Karl & Markus Damme & Arie H, 2017. "Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    2. Taichi Hara & Kenji Nakamura & Makoto Matsui & Akitsugu Yamamoto & Yohko Nakahara & Rika Suzuki-Migishima & Minesuke Yokoyama & Kenji Mishima & Ichiro Saito & Hideyuki Okano & Noboru Mizushima, 2006. "Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice," Nature, Nature, vol. 441(7095), pages 885-889, June.
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    4. Matthias Griebel & Dennis Segebarth & Nikolai Stein & Nina Schukraft & Philip Tovote & Robert Blum & Christoph M. Flath, 2023. "Deep learning-enabled segmentation of ambiguous bioimages with deepflash2," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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