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Molecular characterization of TDP-43's covalent modifications, oligomerization and pathogenesis

Award Number: R21AG098841
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Molecular characterization of TDP-43's covalent modifications, oligomerization and pathogenesis - PROJECT SUMMARY TAR DNA-binding protein 43 (TDP-43) proteinopathies are implicated in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s Disease (AD). The pathological aggregation of TDP-43, often linked to post-translational modifications (PTMs) and impaired clearance mechanisms, remains a major barrier to developing effective therapeutic strategies. Here in this R21 project we aim to systematically characterize TDP-43 aggregation, oligomerization, and extracellular vesicle (EV)-mediated propagation using novel mass spectrometry (MS)-based techniques. We reason that specific covalent modifications and cellular stress conditions promote TDP-43 oligomerization, leading to its pathogenic aggregation and dissemination. To test this hypothesis, we will pursue two specific aims: (1) Define the molecular drivers of TDP-43 aggregation by characterizing its PTMs and interactions under stress conditions using a novel cell-based TDP-43 oligomerization assay and microdroplet reaction-based MS analysis, and (2) Characterize TDP-43 oligomerization and PTMs in EVs isolated from cellular and patient-derived models, assessing their role in intercellular propagation and clearance mechanisms. This exploratory and translational research will provide fundamental insights into TDP-43 proteinopathies by establishing novel methodologies to study its modifications and aggregation dynamics. The anticipated outcome will pave the way for new diagnostic and therapeutic strategies targeting TDP-43-related neurodegenerative diseases.


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: 2026 ( Subtotal = $425,377 )
2026	2026	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	1	9/11/2026	NEW	$425,377
														Subtotal = $425,377

Grand Total All Awards = $425,377

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Molecular characterization of TDP-43's covalent modifications, oligomerization and pathogenesis

Award Number: R21AG098841

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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