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Deubiquitinase USP11 in tau regulation and age-related tauopathy

Award Number: R01AG067741
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Deubiquitinase USP11 in tau regulation and age-related tauopathy - The microtubule-associated protein tau (MAPT) aggregates and accumulates in multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Abnormal tau accumulation leads to oligomerization and formation of neurofibrillary tangles associated with neuronal loss, synaptic dysfunction, and cognitive impairments. While tau undergoes different post-translational modifications including phosphorylation, acetylation, and ubiquitination, ubiquitination is critical for tau turnover via the ubiquitin-proteasome system and autophagy-lysosome pathways. Tau is known to be ubiquitinated by various E3 ligases, including CHIP, TRAF6, and MARCH7. However, very little is known about the role of deubiquitinases (DUBs) in the regulation of tau function, turnover, or tauopathy. The human genome encodes >90 DUBs. Ubiquitin specific peptidases (USPs) are the largest family of DUBs comprising ~50 members in humans. Of these, 27 are expressed in the CNS. Our results from an unbiased screen of CNS-expressed DUBs identified USP11 and USP13 as positive regulators of tau. By taking advantage of mouse models and human postmortem tissues together with molecular, cell biological, imaging, biochemical, electrophysiological, behavioral, viral, histochemical, and recombinant protein toolsets, this proposal will 1. validate the role of USP11 in tau pathogenesis as a function of age and sex in vivo, and 2. determine the mechanistic basis of USP11 in tau stability, aggregation, and toxicity in genetically modified neurons and in vitro systems. Successful conclusion of these studies will determine the significant contribution of USP11, and its DUB activity, to tauopathy in humans and mice as a function of aging and sex. USP11 levels could in part account for potential sex differences in severity of tauopathy in humans and mice. Moreover, these results will provide novel mechanistic insights to USP11 DUB activity, in concert with RanBP9, in tau modification and toxicity.


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 = $402,500 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	6	4/18/2024	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2023 ( Subtotal = $402,500 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	006	5	3/23/2023	NON-COMPETING CONTINUATION	$402,500
2023	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	004	2	2/10/2023	NON-COMPETING CONTINUATION	-$32,220
2023	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	002	3	11/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$373,751
2023	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	005	3	2/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$284,927
2023	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	001	2	11/23/2022	NON-COMPETING CONTINUATION	$32,220
2023	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	1	11/23/2022	NEW	$341,531
2023	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	003	1	2/10/2023	NEW	-$252,707
														Subtotal = $402,500

Issue Date FY: 2022 ( Subtotal = $402,500 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	002	4	4/4/2022	NON-COMPETING CONTINUATION	$402,500
2022	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	004	2	7/12/2022	NON-COMPETING CONTINUATION	-$32,220
2022	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	001	3	1/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$341,530
2022	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	1/13/2022	NON-COMPETING CONTINUATION	-$341,530
2022	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	005	3	7/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,751
2022	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	003	1	7/12/2022	NEW	-$341,531
														Subtotal = $402,500

Issue Date FY: 2021 ( Subtotal = $373,750 )
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	4/9/2021	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2020 ( Subtotal = $373,750 )
2020	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	1	5/22/2020	NEW	$373,750
														Subtotal = $373,750

Grand Total All Awards = $1,955,000

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Deubiquitinase USP11 in tau regulation and age-related tauopathy

Award Number: R01AG067741

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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