C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress

Ilija Melentijevic, Marton L. Toth, Meghan L. Arnold, Ryan J. Guasp, Girish Harinath, Ken C. Nguyen, Daniel Taub, J. Alex Parker, Christian Neri, Christopher V. Gabel, David H. Hall, Monica Driscoll

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77 Scopus citations

Abstract

The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality. Complicating the challenges of neuroprotection, misfolded human disease proteins and mitochondria can move into neighbouring cells via unknown mechanisms, which may promote pathological spread. Here we show that adult neurons from Caenorhabditis elegans extrude large (approximately 4 μm) membrane-surrounded vesicles called exophers that can contain protein aggregates and organelles. Inhibition of chaperone expression, autophagy or the proteasome, in addition to compromising mitochondrial quality, enhances the production of exophers. Proteotoxically stressed neurons that generate exophers subsequently function better than similarly stressed neurons that did not produce exophers. The extruded exopher transits through surrounding tissue in which some contents appear degraded, but some non-degradable materials can subsequently be found in more remote cells, suggesting secondary release. Our observations suggest that exopher-genesis is a potential response to rid cells of neurotoxic components when proteostasis and organelle function are challenged. We propose that exophers are components of a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when dysfunctional or diminished with age, might actively contribute to pathogenesis in human neurodegenerative disease and brain ageing.

Original languageEnglish (US)
Pages (from-to)367-371
Number of pages5
JournalNature
Volume542
Issue number7641
DOIs
StatePublished - Feb 16 2017

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Melentijevic, I., Toth, M. L., Arnold, M. L., Guasp, R. J., Harinath, G., Nguyen, K. C., Taub, D., Parker, J. A., Neri, C., Gabel, C. V., Hall, D. H., & Driscoll, M. (2017). C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature, 542(7641), 367-371. https://doi.org/10.1038/nature21362