Alzheimer's disease is ravaging the world's elderly population and creating a heath and societal burden thatappears likely to increase. Basic research can inform on mechanisms relevant to late onset neurodegenerativedisease and suggest avenues of treatment. Healthy aging of the brain requires meticulous maintenance ofprotein synthesis/folding/degradation systems, and this capacity is often disrupted in neurodegenerativedisease. Recently it has come to be appreciated that disease neurons can produce toxic products likeaggregated proteins that can be taken up by neighboring cells—there is speculation that this mechanism mightbe involved in disease spread within the brain. How neurons generate and send out large-sized extracellularmaterial in vivo is an open 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, aswell as labeled aggregates within them, can easily be visualized in the living animal. We have unexpectedlydiscovered that some C. elegans neurons can exude large packets we call “exophers”. The contents of thesedramatically expelled exophers can contain introduced human disease protein aggregates. Multipleapproaches to exaggerating protein folding stresses in those neurons, including over-expressing humanAlzheimer's disease associated fragment A 1-42, and genetically or pharmacologically impairing branches ofprotein homeostasis, increase exopher formation. Aggregated proteins extruded in exophers can be taken upby distant cells.We hypothesize that we have identified a previously unrecognized alternative route for adult neurons to clearprotein aggregates. We speculate that this mechanism, and the associated mechanism of release and uptakeby surrounding cells, is conserved across species and related to currently unknown mechanisms operating inhuman brain relevant to neurodegenerative disease.We propose to exploit the considerable advantages of the C. elegans model system (transparent body, easygenetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to advanceunderstanding of exopher biology. Our goals are to: 1) probe the biology of old age exophers (induction,functionality, and longevity gene interface); 2) screen human neurodegenerative disease-related genes forroles in C. elegans exopher formation; 3) begin to decipher the mechanism whereby AIP-1, needed forexopher production and known to protect against broad proteotoxicity, influences exopher-genesis underproteo-stress.Our work should inform on a novel pathway of cell maintenance relevant to both healthy brain aging and aneurodegenerative disease, defining a new area for study and for development of clinical interventions.
|Effective start/end date||8/1/17 → 3/31/22|
- National Institutes of Health (NIH)