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A synthetic biology approach for tau post-translational modifications in AD

Award Number: R01AG083876
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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A synthetic biology approach for tau post-translational modifications in AD - Oligomeric forms of tau are the primary source of neurotoxicity in a wide range of neurodegenerative diseases. Structural studies of pathological tau aggregates isolated from tauopathy patient brains have uncovered a diversity of disease-specific tau conformations and structural polymorphs, but the mechanism for how they misfold into pathogenic species remains unknown. Here we aim to test a long-standing hypothesis that post- translational modifications (PTMs), such as phosphorylation and acetylation at disease-associated sites, mediate tau oligomerization, structural polymorph-dependent propagation, and neurotoxicity. We propose a bottom-up approach for directly assessing the impact of pre-defined, disease-associated phosphorylation and acetylation of full-length human tau. For the first time, we demonstrate that a state-of-the-art synthetic biology approach enables the production of recombinant site-specifically phosphorylated tau (rp-tau), and that rp-tau with a single modification is sufficient to adopt pathological conformations. This new capability will be expanded to include site-specific lysine acetylation of tau to produce full-length tau with defined PTMs (including simultaneous phospho- and acetyl-) implicated in Alzheimer’s disease (AD) and AD-related dementias (ADRD). The new reagents developed here will be used to determine the impact of site-specific tau PTMs on tau conformation using cryo-EM, microtubule binding, oligomerization, neurotoxicity, and tau seeding. We will generate monoclonal antibodies against tau with defined PTMs and AD/ADRD relevant conformations validated through cryo-EM. The impact of the project will be to provide transferrable resources to test tau PTMs with unprecedented resolution and uncover the molecular signature and mechanisms that mediate tau oligomerization, conformational change, and seeding.


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: 2025 ( Subtotal = $590,590 )
2025	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	3	5/7/2025	NON-COMPETING CONTINUATION	$542,379
2025	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	001	3	6/17/2025	NON-COMPETING CONTINUATION	$48,211
														Subtotal = $590,590

Issue Date FY: 2024 ( Subtotal = $603,934 )
2024	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	2	6/3/2024	NON-COMPETING CONTINUATION	$603,934
														Subtotal = $603,934

Issue Date FY: 2023 ( Subtotal = $651,090 )
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	1	8/24/2023	NEW	$651,090
														Subtotal = $651,090

Grand Total All Awards = $1,845,614

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A synthetic biology approach for tau post-translational modifications in AD

Award Number: R01AG083876

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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