Fig 5. (A) Relative sizes of extracellular vesicle types. (B) ALM mechanosensory neuron soma (left) ejecting Exposer vesicle (right). mCherry fill with concentration with lysosomes. Mitochondria marked in green. Nuclei in blue.
Fig 6. Time series of hypodermic cell with labeled F-actin (green) engaging in phagocytosis of the Exopher bud emerging from an mCherry (red) labeled ALM neuron.
Healthy aging of the brain is highly dependent upon a range of protein quality control systems, and such quality control capacity is often disrupted in neurodegenerative disease. Recently it has come to light that diseased neurons can transfer toxic products such as aggregated proteins to neighboring cells, likely leading to spreading pathology within the brain. How neurons generate and send out extracellular material in vivo is a question that must be addressed as we consider therapeutic intervention. We have been collaborating closely with Monica Driscoll’s lab to understand the mechanisms behind formation of a new class of neuron-derived giant vesicles called “exophers” that carry toxic aggregates and organelles out of the cell and are induced by several cell stressors (Fig. 5) (Cooper et al., 2021; Arnold et al., 2023). Similar mechanisms of giant vesicle budding and transfer of aggregates, lipids, and damaged organelles have been recently identified in C. elegans muscle, mouse cardiomyocytes, and mouse and human brain, strongly implying that discoveries we make about how this process operates in C. elegans will be widely relevant across species and tissues. Our contributions to this work have discovered specific mechanisms for triggering exopher production, such as association of intermediate filaments with aggresomes, and specific pathways in the uptake and degradation of exophers by the neighboring hypodermal cell (Fig.6) (Cooper et al., 2021; Wang et al., 2023; Arnold et al., 2023). Importantly our studies identified a surprisingly strict and non-autonomous requirement for phagocytic recognition of nascent exophers by the hypodermal cell for the neuron to complete formation of the exopher, a mechanism that we liken to synaptic pruning by glia (Wang et al., 2023).
Related Publications
Intermediate filaments associate with aggresome-like structures in proteostressed C. elegans neurons and influence large vesicle extrusions as exophers Arnold ML, Cooper J, Androwski R, Ardeshna S, Melentijevic I, Smart J, Guasp RJ, Nguyen KCQ, Bai G, Hall DH, Grant BD, Driscoll M. Intermediate filaments associate with aggresome-like structures in proteostressed C. elegans neurons and influence large vesicle extrusions as exophers. Nat Commun. 2023;14(1):4450. Epub 20230724. doi: 10.1038/s41467-023-39700-1. PubMed PMID: 37488107; PMCID: PMC10366101. [PubMed]
Large vesicle extrusions from C. elegans neurons are consumed and stimulated by glial-like phagocytosis activity of the neighboring cell Wang Y, Arnold ML, Smart AJ, Wang G, Androwski RJ, Morera A, Nguyen KCQ, Schweinsberg PJ, Bai G, Cooper J, Hall DH, Driscoll M, Grant BD. Large vesicle extrusions from C. elegans neurons are consumed and stimulated by glial-like phagocytosis activity of the neighboring cell. Elife. 2023;12. Epub 20230302. doi: 10.7554/eLife.82227. PubMed PMID: 36861960; PMCID: PMC10023159. [PubMed]
Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling Cooper JF, Guasp RJ, Arnold ML, Grant BD, Driscoll M. Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling. Proc Natl Acad Sci U S A. 2021;118(36). doi: 10.1073/pnas.2101410118. PubMed PMID: 34475208; PMCID: PMC8433523. [PubMed]
Quantitative Approaches for Scoring in vivo Neuronal Aggregate and Organelle Extrusion in Large Exopher Vesicles in C. elegans Arnold ML, Cooper J, Grant BD, Driscoll M. Quantitative Approaches for Scoring in vivo Neuronal Aggregate and Organelle Extrusion in Large Exopher Vesicles in C. elegans. J Vis Exp. 2020(163). Epub 20200918. doi: 10.3791/61368. PubMed PMID: 33016946; PMCID: PMC7805482. [PubMed]
