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

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Basic research can inform on mechanisms relevant to late onset neurodegenerative disease and suggest avenues of treatment. Healthy aging of the brain requires meticulous maintenance of protein synthesis/folding/degradation systems, and this capacity is often disrupted in neurodegenerative disease. Recently it has come to be appreciated that diseased neurons can produce toxic products like aggregated proteins 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 send out extracellular material in vivo is a question that must be addressed as we consider therapeutic intervention. We study the aging nervous system in the simple animal model C. elegans, in which individual neurons, as well as labeled protein aggregates within them, can easily be visualized in the living organism. We have unexpectedly discovered that some C. elegans neurons can extrude large packets we call “exophers”. The contents of these dramatically expelled exophers can contain introduced human disease protein aggregates. Multiple approaches to exaggerating protein-folding stresses in those neurons, including over-expressing human Alzheimer’s disease fragment Ab1-42 or Huntington’s disease-associated polyQ protein, and genetically or pharmacologically impairing branches of protein homeostasis, increase exopher formation. Aggregated proteins extruded in exophers travel through a neighboring cell, which we think attempts to degrade the expelled neurotoxic aggregates, but the non-degradable trash can pass through to be taken up by distant cells. We hypothesize that exopher production is a previously unrecognized alternative route for adult neurons to clear protein aggregates. We speculate that this mechanism, and the associated mechanism of release and uptake by surrounding cells, is conserved across species and may be analogous to currently unknown mechanisms operating in human brain relevant to neurodegenerative disease. 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 advance understanding of exopher biology. Our goals are to: 1) define the genetic and cell biological events that are critical for exopher formation by probing motors, cytoskeletal factors and membrane trafficking agents that we know are important; 2) learn about the exodus of the extruded exopher as it transits though neighboring tissues, defining how the invading exopher is recognized, reacted to, and, if resistant, thrown out again. Our work should inform on a novel pathway of proteostasis control relevant to both healthy brain aging and neurodegenerative disease, defining a new area for study and for development of clinical interventions.