# Defining Roles of Genetics and Age in Extrusion of Neurotoxic Aggregates

> **NIH NIH R37** · RUTGERS, THE STATE UNIV OF N.J. · 2022 · $113,723

## Abstract

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 Abeta1-42, 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 are exploiting 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.
A fascinating recent development is our finding that tricks that shut down the stressed neurons
activity or connection can actually increase exopher production. We request a Diversity
Supplement to enable an outstanding researcher who manages ADHA to pursue details of this
biology by
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.

## Key facts

- **NIH application ID:** 10621615
- **Project number:** 3R37AG056510-06S1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** MONICA A. DRISCOLL
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $113,723
- **Award type:** 3
- **Project period:** 2017-08-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10621615

## Citation

> US National Institutes of Health, RePORTER application 10621615, Defining Roles of Genetics and Age in Extrusion of Neurotoxic Aggregates (3R37AG056510-06S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10621615. Licensed CC0.

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