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Role of oligomeric TDP-43 aggregate intermediates in ALS and frontotemporal dementia

Award Number: R01NS114289
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: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Role of oligomeric TDP-43 aggregate intermediates in ALS and frontotemporal dementia - The goal of this grant is to elucidate key mechanisms of TDP-43 aggregation by uncovering how this process leads to pathology and neurotoxicity. TDP-43 aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and half of frontotemporal dementia (FTD) cases. In addition, TDP-43 lesions are a secondary pathology in approximately 50% of Alzheimer's disease. A major goal in combatting ALS and FTD has been to reduce the accumulation of TDP-43 inclusions by developing strategies to prevent or reverse TDP-43 aggregation. Recognizing this, we established strategic methods to study the aggregation of this RNA binding protein using purified TDP-43 and have identified previously unknown aggregate intermediates. These are early stage oligomers that share key characteristics with toxic oligomeric species of well-studied proteins linked to neurodegeneration, including Tau, amyloid-β and α-synuclein. These TDP-43 aggregate intermediates are capable of seeding de novo intracellular TDP-43 aggregation and their formation is accelerated by ALS-linked mutations. Our recent findings provide the unique opportunity to shed light on fundamental mechanisms of TDP-43 aggregation, determine their role in pathogenesis and provide models to block TDP-43 pathology. Aim 1 will establish the presence of TDP-43 oligomers in cellular models of aggregation and in ALS and FTD- derived tissue. In particular, we will examine recruitment of the intermediates to cytoplasmic stress granules, which are protein-RNA rich bodies considered to be crucibles of pathological aggregation. This will be achieved using our established methods of detection and by developing antibodies specific for the intermediate complexes. To establish the role of the newly found TDP-43 intermediates in aggregation and pathogenesis, Aim 2 will define the molecular determinants of assembly and test how disease-associated conditions upregulate this process. After identifying the protein regions mediating oligomerization, we will ask whether aggregation and intracellular seeding function decrease upon disruption of the newly identified epitopes. The ability of TDP-43 aggregates to act as agents of pathological spread in disease is strongly suggested by recent findings that FTD-derived extracts seed and propagate TDP-43 pathology in mouse brain. Aim 3 will test whether TDP-43 aggregates alone can indeed initiate de novo aggregation and propagation of pathology in vivo. We will analyze the spread of TDP-43 pathology upon injection of early and late stage TDP-43 aggregates derived from purified protein in the brain of mice. This will establish whether TDP-43 aggregates, and TDP-43 oligomers in particular, are primary sources of nucleation and neurotoxicity. Furthermore, these studies we will determine whether this propagation directly correlates with increased neurodegeneration. With the successful completion of this grant, we will: a) define fundamental processes in TDP-43 aggregation; b) establish in vitro and in vivo models to forestall neurotoxicity in ALS and FTD; and c) provide unprecedented tools for the development of diagnostic markers of disease.


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 = $378,750 )
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/11/2024	NON-COMPETING CONTINUATION	$37,875
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/17/2024	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $378,750

Issue Date FY: 2023 ( Subtotal = $378,750 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/16/2023	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2022 ( Subtotal = $379,932 )
2022	2022	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/20/2022	NON-COMPETING CONTINUATION	$341,938
2022	2022	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/1/2022	NON-COMPETING CONTINUATION	$37,994
														Subtotal = $379,932

Issue Date FY: 2021 ( Subtotal = $380,396 )
2021	2021	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/28/2021	NON-COMPETING CONTINUATION	$380,396
														Subtotal = $380,396

Issue Date FY: 2020 ( Subtotal = $393,229 )
2020	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	4/17/2020	NEW	$0
2020	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/20/2020	NEW	$393,229
														Subtotal = $393,229

Grand Total All Awards = $1,911,057

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Role of oligomeric TDP-43 aggregate intermediates in ALS and frontotemporal dementia

Award Number: R01NS114289

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: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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