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Unraveling the Aggregation of TDP43 Fragments Associated with ALS and FTD: Insights into Protein Quality Control Mechanisms and Cellular Vulnerability

Award Number: R15NS095317
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Unraveling the Aggregation of TDP43 Fragments Associated with ALS and FTD: Insights into Protein Quality Control Mechanisms and Cellular Vulnerability - Project Summary As life expectancy increases, so does the prevalence of Alzheimer’s disease (AD) and AD-related dementias (ADRD), posing significant healthcare burdens. These conditions are linked to aggregates of specific proteins or proteolytic fragments in central nervous system cells. For example, C-terminal fragments (CTFs) of the TAR DNA-binding protein 43 (TDP43) are the primary components of protein inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and are also associated with ADRD. These fragments are generated by increased protein cleavage or defects in protein quality control (PQC) systems, such as the pathways involved in protein degradation. Despite ongoing research, the processes that produce toxic protein fragments and the cellular mechanisms that respond to them are not fully understood. Our lab specializes in protein degradation through the ubiquitin-proteasome system (UPS), particularly with respect to proteolytic fragments. We have studied multiple disease-linked CTFs of TDP43 and found that their N-termini, determined by cleavage sites, influence their metabolism, aggregation potential, and toxicity. Additionally, we have identified two distinct UPS pathways that recognize specific features of these fragments and help protect cells from aggregation. This suggests that a cell’s vulnerability to CTF aggregation depends on how the fragment is generated and the PQC pathways active within the cell. In this project, we will investigate a third potential mechanism for removing aggregation-prone fragments linked to neurodegeneration and assess the susceptibility of different brain cell types to protein cleavage and aggregation. This research will deepen our understanding of neurodegenerative diseases and provide opportunities for student involvement in cutting-edge research at Texas Woman’s University.


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 = $471,114 )
2025	2025	TEXAS WOMANS UNIVERSITY	304 ADMINISTRATION DRIVE	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/10/2025	COMPETING CONTINUATION	$476,973
2025	2021	TEXAS WOMANS UNIVERSITY	304 ADMINISTRATION DRIVE	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/4/2025	COMPETING CONTINUATION	-$5,859
														Subtotal = $471,114

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	TEXAS WOMANS UNIVERSITY	304 ADMINISTRATION DRIVE	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/16/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $72,067 )
2022	2022	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/1/2022	SUPPLEMENT FOR EXPANSION	$72,067
														Subtotal = $72,067

Issue Date FY: 2021 ( Subtotal = $385,343 )
2021	2021	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/26/2021	COMPETING CONTINUATION	$534
2021	2021	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/3/2021	COMPETING CONTINUATION	$385,343
2021	2016	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/12/2020	NEW	-$534
														Subtotal = $385,343

Issue Date FY: 2016 ( Subtotal = $372,857 )
2016	2016	TEXAS WOMANS UNIVERSITY	P.O. BOX 425439	DENTON	TX	76204	DENTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/14/2016	NEW	$372,857
														Subtotal = $372,857

Grand Total All Awards = $1,301,381

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Unraveling the Aggregation of TDP43 Fragments Associated with ALS and FTD: Insights into Protein Quality Control Mechanisms and Cellular Vulnerability

Award Number: R15NS095317

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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