Understanding the Exopher: A Novel Mechanism for Extrusion of Neurotoxic Content

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DESCRIPTION (provided by applicant): Healthy aging of the brain requires meticulous maintenance of protein synthesis/degradation systems as well as sustained organelle function. Recently it has come to be appreciated that neurons can produce products that can be taken up by neighboring cells-there is speculation that this mechanism might be involved in disease spread within the brain. How neurons generate and take up large-sized extracellular material in vivo is an open question. We study the aging nervous system in the simple animal model C. elegans, in which individual neurons, as well as aggregates and mitochondria within them, can easily be visualized in the living cell. We have unexpectedly discovered that some C. elegans neurons can exude large packets of cytoplasm ("exophers"). The contents of these dramatically expelled packets can contain introduced human disease protein aggregates or mitochondria. Preliminary data suggest they can be taken up by surrounding cells. We hypothesize that we have identified a novel alternative route for adult neurons to clear protein aggregates and defective organelles. We speculate that this mechanism, and the associated mechanism of release and uptake by surrounding cells, is conserved across species and related to currently unknown mechanisms operating in human brain relevant to disease and disrupted in aging. We propose to exploit the considerable advantages of the C. elegans model system (transparent body, easy genetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to markedly advance understanding of exopher biology. Our goals are to understand the mechanisms by which exophers are generated and the factors that increase their production; to test whether exopher production is beneficial to the neuron that makes it; to define the relationship of exopher production to aging; and to probe mechanisms, and consequences of, exopher transfer to neighboring cells. Our work should document a novel pathway of cell maintenance relevant to both healthy brain aging and a wide spectrum of neurodegenerative diseases, defining a new area for study and for development of therapeutic interventions.