Alzheimer's disease is ravaging the world's elderly population and creating a heath and societal burden that appears likely to increase. 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 disease 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 large-sized extracellular material 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, as well as labeled aggregates within them, can easily be visualized in the living animal. We have unexpectedly discovered that some C. elegans neurons can exude 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 associated fragment A 1-42, and genetically or pharmacologically impairing branches of protein homeostasis, increase exopher formation. Aggregated proteins extruded in exophers can be taken up by distant cells. We hypothesize that we have identified 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 related 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) probe the biology of old age exophers (induction, functionality, and longevity gene interface); 2) screen human neurodegenerative disease-related genes for roles in C. elegans exopher formation; 3) begin to decipher the mechanism whereby AIP-1, needed for exopher production and known to protect against broad proteotoxicity, influences exopher-genesis under proteo-stress. Our work should inform on a novel pathway of cell maintenance relevant to both healthy brain aging and a neurodegenerative disease, defining a new area for study and for development of clinical interventions.

Public Health Relevance

We discovered a previously unrecognized mechanism by which neurons protect against effects of protein aggregation?they physically throw out their threatening trash in membrane-surrounded large vesicles (exophers) for uptake by remote cells. ?Exopher-genesis? is increased when neurons are subjected to proteostasis challenges, including expression of human Alzheimer's disease fragment A 1-42. Since we propose that exopher-genesis is a conserved pathway for maintaining neuronal health and we speculate that older age dysfunction of the exopher pathway might contribute to neurodegeneration and spread of neurotoxic species, dissection of the exopher mechanism should provide novel insight on Alzheimer's disease-relevant pathology that might be manipulated for therapeutic benefit.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
1R37AG056510-01
Application #
9367829
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
2017-08-01
Project End
2022-03-31
Budget Start
2017-08-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rutgers University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
Piscataway
State
NJ
Country
United States
Zip Code
08854