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Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology

Award Number: R01AG084680
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology - Pathological tau protein accumulates in neuronal lesions and constitutes one of the defining diagnostic hallmarks of Alzheimer’s disease and related tauopathy disorders. Tau neuropathology correlates with severity of dementia in Alzheimer’s disease. However, tau related dysfunction and aggregation drives neurodegenerative changes by an incompletely understood molecular mechanism. Previous work has demonstrated that RNA binding proteins impact tau function and aggregation in model systems and disease states. In quantitative studies, we have shown that tau binds RNA with high affinity but low sequence specificity. Tau RNA complexes (TRCs) form high molecular weight oligomeric tau species that may be on pathway to formation of mature fibrillar aggregates. We have produced a TRC recognizing monoclonal antibody (TRC35) that detects a disease relevant pathological tau conformation. We hypothesize that RNA and microtubules (MTs) compete for tau binding with TRC formation driving neuropathological tau accumulation, fibril deposition, and neurodegeneration while MT binding promotes neuronal homeostasis. We propose 3 specific aims to determine the impact of tau RNA binding activity on disease pathogenesis. We will 1) dissect the molecular features of tau RNA binding activity and interplay with tau microtubule binding activity; 2) map the abundance, distribution, and composition of TRC35+ lesions in tauopathy disorders; and 3) measure the impact of tau RNA complex formation on neurodegeneration. Completion of the proposed project will impact the field by integrating tau RNA binding functions with known tau roles in MT stabilization. We will also gain significant understanding of the molecular mechanisms involved in disease relevant pathological tau aggregation and deposition in tauopathy disorders. We will further measure the contribution of tau/RNA complexes to the neurodegeneration observed in tauopathies.


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 = $661,062 )
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	3	7/10/2025	NON-COMPETING CONTINUATION	$661,062
														Subtotal = $661,062

Issue Date FY: 2024 ( Subtotal = $647,228 )
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	001	2	6/21/2024	NON-COMPETING CONTINUATION	$647,228
2024	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	1	10/11/2023	NEW	$0
														Subtotal = $647,228

Issue Date FY: 2023 ( Subtotal = $638,837 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	1	9/26/2023	NEW	$638,837
														Subtotal = $638,837

Grand Total All Awards = $1,947,127

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Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology

Award Number: R01AG084680

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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