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

Award Number: R01AG047101
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	9	4/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $559,773 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	9	1/7/2022	NON-COMPETING CONTINUATION	$503,794
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	9	4/21/2022	NON-COMPETING CONTINUATION	$55,979
														Subtotal = $559,773

Issue Date FY: 2021 ( Subtotal = $559,772 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	8	2/5/2021	NON-COMPETING CONTINUATION	$559,772
														Subtotal = $559,772

Issue Date FY: 2020 ( Subtotal = $614,746 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	7	1/23/2020	NON-COMPETING CONTINUATION	$614,746
														Subtotal = $614,746

Issue Date FY: 2019 ( Subtotal = $621,566 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	6	11/9/2018	NON-COMPETING CONTINUATION	$621,566
														Subtotal = $621,566

Issue Date FY: 2018 ( Subtotal = $635,318 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	002	5	8/30/2018	COMPETING CONTINUATION	$42,378
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	5	12/13/2017	COMPETING CONTINUATION	$592,940
2018	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	4	12/12/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $635,318

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	3	1/31/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $309,132 )
2016	2016	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	4	7/5/2016	EXTENSION WITH OR WITHOUT FUNDS	$309,132
														Subtotal = $309,132

Issue Date FY: 2015 ( Subtotal = $299,124 )
2015	2015	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	3	7/3/2015	NON-COMPETING CONTINUATION	$299,124
														Subtotal = $299,124

Issue Date FY: 2014 ( Subtotal = $332,981 )
2014	2014	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	2	8/29/2014	SUPPLEMENT FOR EXPANSION	$25,334
2014	2014	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	2	6/24/2014	NON-COMPETING CONTINUATION	$307,647
														Subtotal = $332,981

Issue Date FY: 2013 ( Subtotal = $306,944 )
2013	2013	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	1	9/20/2013	NEW	$306,944
														Subtotal = $306,944

Grand Total All Awards = $4,239,356

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

Award Number: R01AG047101

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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