C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress.
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.
Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Ilija
I
Melentijevic
Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Marton L
ML
Toth
Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Meghan L
ML
Arnold
Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Ryan J
RJ
Guasp
Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Girish
G
Harinath
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Ken C
KC
Nguyen
Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.|Boston University Photonics Center, Boston, Massachusetts 02215, USA.
Daniel
D
Taub
Département de Neurosciences, Université de Montréal CRCHUM, Montréal H2X 0A9, Canada.
J Alex
JA
Parker
CNRS, UMR 8256, Brain-C team, Paris, France, and Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France.
Christian
C
Neri
Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.|Boston University Photonics Center, Boston, Massachusetts 02215, USA.
Christopher V
CV
Gabel
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
David H
DH
Hall
Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Monica
M
Driscoll
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000166:cytology / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D000066829:Neuroprotection / Q000502:physiology*; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates
D018832:Molecular Chaperones; D066329:Protein Aggregates; D046988:Proteasome Endopeptidase Complex