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Evaluating Protein Quality Control in the Toxicity of TDP43 Fragments Associated with ALS and FTD

Award Number: R15NS095317
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary People are living longer, which increases their risk of developing neurodegenerative disorders. Such disorders can be characterized by the accumulation and aggregation of specific proteins in the brain. These aggregates often contain protein fragments produced by increases in protein cleavage or defects in protein quality control (PQC) systems such as regulated protein degradation. We do not know how all protein fragments are metabolized and how they cause toxicity to neurons. Our overall goal is to understand the effects of protein aggregates on normal cell function and to identify cellular pathways that prevent toxicity. Previously, we found that the N-degron pathway can degrade specific C-terminal fragments (CTFs) associated with neurodegenerative disorders. We also found that the N- termini of CTFs influence their metabolism, tendency to aggregate, and the morphology of their aggregates. In recent work, we found that Bcl-2-associated athanogene 6 (BAG6) interacts with CTFs linked to disease and increases their solubility. BAG6 is a component of a chaperone complex that determines the fate of unfolded proteins. In this work, we developed new methods to examine CTFs with natural N-termini in cultured neurons and in transgenic mouse models. Using these methods, we will determine how BAG6 regulates the metabolism of CTFs that are prone to aggregate. We will also establish whether aggregates of CTFs cause toxicity that leads to neurodegeneration. This project will help us better understand how protein fragments are toxic and how cellular PQC guards against neurodegeneration.


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 = $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 = $830,267

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Evaluating Protein Quality Control in the Toxicity of TDP43 Fragments Associated with ALS and FTD

Award Number: R15NS095317

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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