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Cited by 454Autophagy in Disease and TherapyGenetics, Aging, and Longevity in Model OrganismsCellular transport and secretion

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

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Melentijevic, Ilija, Toth, Marton L., Arnold, Meghan L., Guasp, Ryan J., Harinath, Girish, Nguyen, Ken C., Taub, Daniel, Parker, J. Alex +4 more·2017·Nature
DOI 10.1038/nature21362PMC PMC5336134
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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.

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  • Microglia in the substantia nigra have a much higher lysosomal content compared to other basal ganglia nuclei.

    “Specifically, microglia in the substantia nigra have a much higher lysosomal content compared to other basal ganglia nuclei.109”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [109]

    The Extended Data passages describe lysosomes in C. elegans touch neurons and exophers, not microglia. Searches for substantia nigra, basal ganglia, and comparative microglial lysosomal content found no passage addressing the claim. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Cited by

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Authors
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.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • Albert Einstein College of Medicine (US)
  • Boston University (US)
  • Université de Montréal (CA)
Corresponding author
Driscoll, Monica
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2017-02
Volume
542
Issue
7641
Pages
367-371
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature21362
PMC
PMC5336134
OpenAlex
W2587038123
Cited by
454
References
4
Citations by year
2026: 45 · 2025: 72 · 2024: 69 · 2023: 55 · 2022: 36 · 2021: 44 · 2020: 42 · 2019: 34 · 2018: 29 · 2017: 27 · 2014: 1
FWCI
28.28
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (P40OD010440, R24OD010943)
  • National Institute on Aging (R01AG046358, R01AG047101)
  • National Institute of General Medical Sciences (T32GM008339)
  • National Institute of Neurological Disorders and Stroke (R01NS077929)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD071593)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
protein aggregates, mitochondrial dysfunction, neuronal proteostasis, mitochondrial quality control, autophagy, proteasome, molecular chaperones, neurodegenerative diseases, brain aging, Caenorhabditis elegans neurons
MeSH terms
Neuroprotection, Aging, Animals, Autophagy, Cytoplasm, Mitochondria, Neurons, Oxidation-Reduction, Caenorhabditis elegans, Molecular Chaperones, Neurodegenerative Diseases, Proteasome Endopeptidase Complex, Cell-Derived Microparticles, Protein Aggregates

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