Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy

Amy-Jayne Hutchings, Bita Hambrecht, Alexander Veh, Neha Jadhav Giridhar, Abdolhossein Zare, Christina Angerer, Thorben Ohnesorge, Maren Schenke, Bhuvaneish T. Selvaraj, Siddharthan Chandran, Jared Sterneckert, Susanne Petri, Bettina Seeger, Michael Briese, Christian Stigloher, Thorsten Bischler, Andreas Hermann, Markus Damme, Michael Sendtner and Patrick Lüningschrör ()
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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
Bhuvaneish T. Selvaraj: University of Edinburgh
Siddharthan Chandran: University of Edinburgh
Jared Sterneckert: Center for Regenerative Therapies 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
Markus Damme: Christian-Albrechts-University Kiel
Michael Sendtner: University Hospital Würzburg
Patrick Lüningschrör: University Hospital Würzburg

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52875-5

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