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Uncovering the roles of ubiquitination and the ESCRT pathway in degradative sorting of SV proteins.

Award Number: R01NS080967
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Synaptic vesicles (SVs) are highly specialized organelles that store and release neurotransmitters. The accumulation of old or damaged proteins on SVs compromises neurotransmission and can lead to dysfunctional neural circuits and networks. Indeed, recent studies have shown that mutations in genes that regulate SV protein degradation are associated with neurological and neurodegenerative disorders, demonstrating the critical importance of SV protein turnover for nervous system health. Yet the molecular mechanisms responsible for SV turnover and degradation remain poorly understood. The overall goal of this project is to elucidate these mechanisms, providing critical insights into the etiology of diseases that afflict millions of Americans. Our recent work has shown that the ESCRT pathway mediates the activity-dependent degradation of SV membrane proteins. The ESCRT pathway comprises a series of protein complexes that sequentially recruit ubiquitinated cargo and catalyze the formation of multivesicular bodies (MVBs) for delivery of these cargo to lysosomes. Intriguingly, we find that increased neuronal firing stimulates the activation of de/ubiquitinating enzymes at the synapse, as well as the motility of axonal transport vesicles carrying initial ESCRT protein Hrs, and their recruitment to SV pools. We hypothesize that these events are critical rate- limiting steps for activity-dependent turnover of SV membrane proteins. We will test this hypothesis with three aims. In Aim 1, we will evaluate the role of de/ubiquitination in the recycling of SV membrane proteins. Here, we will use biochemical and fluorescence imaging assays to evaluate how ubiquitination regulates SV protein recycling vs. degradation in hippocampal neurons. We will also investigate whether the deubiquitinating enzyme UCHL1 is necessary for maintaining SV proteins on recycling SVs, counteracting their degradative sorting. In Aim 2, we will characterize Hrs vesicles and the impact of Hrs on downstream ESCRT protein recruitment to SV pools. We will use super-resolution fluorescence/electron microscopy and proximity biotinylation to characterize the morphology and molecular composition of these vesicles, and Hrs gain- and loss-of-function combined with live imaging to determine whether the recruitment of downstream ESCRT proteins to SV pools requires Hrs. In Aim 3, we will investigate the mechanisms of activity-dependent Hrs recruitment to SV pools. We will test the roles of specific kinesins in the axonal transport of Hrs, and test whether its recruitment to SV pools requires the lipid PI(3)P, the presence of ubiquitinated proteins, and/or the small GTPase Rab35. Together, these studies will uncover fundamental mechanisms underlying SV proteostasis in neurons.


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: 2023 ( Subtotal = $377,230 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/8/2023	NON-COMPETING CONTINUATION	$377,230
														Subtotal = $377,230

Issue Date FY: 2022 ( Subtotal = $382,577 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/18/2022	NON-COMPETING CONTINUATION	$344,317
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	6/24/2022	NON-COMPETING CONTINUATION	$38,260
														Subtotal = $382,577

Issue Date FY: 2021 ( Subtotal = $478,327 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/4/2021	NON-COMPETING CONTINUATION	$478,327
														Subtotal = $478,327

Issue Date FY: 2020 ( Subtotal = $430,698 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/24/2020	NON-COMPETING CONTINUATION	$374,023
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	7/10/2020	SUPPLEMENT FOR EXPANSION	$56,675
														Subtotal = $430,698

Issue Date FY: 2019 ( Subtotal = $381,145 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/24/2019	COMPETING CONTINUATION	$381,145
														Subtotal = $381,145

Issue Date FY: 2018 ( Subtotal = -$1 )
2018	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/20/2018	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2017 ( Subtotal = $349,401 )
2017	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	6/6/2017	NON-COMPETING CONTINUATION	$34,941
2017	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	5/5/2017	NON-COMPETING CONTINUATION	$314,460
2017	2016	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/9/2017	EXTENSION WITH OR WITHOUT FUNDS	$76,058
2017	2015	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/9/2017	NON-COMPETING CONTINUATION	-$76,058
														Subtotal = $349,401

Issue Date FY: 2016 ( Subtotal = $348,822 )
2016	2016	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/6/2016	EXTENSION WITH OR WITHOUT FUNDS	$348,822
														Subtotal = $348,822

Issue Date FY: 2015 ( Subtotal = $348,261 )
2015	2015	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/1/2015	NON-COMPETING CONTINUATION	$348,261
														Subtotal = $348,261

Issue Date FY: 2014 ( Subtotal = $344,241 )
2014	2014	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/28/2014	SUPPLEMENT FOR EXPANSION	-$37,332
2014	2014	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/29/2014	NON-COMPETING CONTINUATION	$344,240
2014	2014	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/14/2014	SUPPLEMENT FOR EXPANSION	$37,333
														Subtotal = $344,241

Issue Date FY: 2013 ( Subtotal = $347,055 )
2013	2013	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW Memorial LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/5/2013	NEW	$347,055
														Subtotal = $347,055

Grand Total All Awards = $3,787,756

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Uncovering the roles of ubiquitination and the ESCRT pathway in degradative sorting of SV proteins.

Award Number: R01NS080967

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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