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Effects of TDP-43 Proteinopathy on Retrotransposon Activation and Cell-Type Specific Vulnerability in a Mammalian Model of Alzheimer's and Related Dementias

Award Number: R01AG079898
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT ABSTRACT: This proposal will test key aspects of the roles of TDP-43 proteinopathy and endogenous retroviruses in the pathology of amyotrophic lateral sclerosis/frontotemporal dementia and Alzheimer’s and related dementias. This proposal will test, in a mammalian model, the hypothesis that reactivation of retrotransposons (RTEs) is a means for neurodegeneration and dementia through the following actions: (1) TDP-43 toxicity causes RTE activation in neurons and glia, (2) the effects of TDP-43 on RTEs are non-cell autonomous, and (3) RTEs contribute to toxicity and non-cell autonomy. This proposal will also establish a first-ever mammalian platform to investigate TDP- 43 and RTEs in an established neurodegeneration/dementia model, the TDP-43-Q331K mutant mouse. Two complementary approaches will be used to investigate the role of TDP-43 in retrotransposon biology. First, a low-expressing Tg-hTDP-43-Q331K, but not a low-expressing Tg-hTPD43-WT model, develops motor dysfunction and loss of spinal motor neurons. Second, high overexpression of TDP-43 in either neurons or astrocytes through localized AAV brain injections provides the means to investigate non-cell autonomous signaling between neurons and glia. By driving overexpression only in neurons or glia with AAV virus, the effects of TDP-43 pathology on RTE expression will also be determined, and the non-cell autonomous spread of toxic effects between these cell types. Finally, the relationship of soluble oligomerization to the disease phenotypes will be determined, allowing the pursuit of additional translational investigations into the potential use of reverse transcriptase inhibitors and disaggregase compounds for alleviating or delaying progression 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 = $536,013 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Aging Research	001	2	5/1/2024	NON-COMPETING CONTINUATION	$53,600
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Aging Research	000	2	11/7/2023	NON-COMPETING CONTINUATION	$482,413
														Subtotal = $536,013

Issue Date FY: 2023 ( Subtotal = $518,787 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Aging Research	000	1	11/24/2022	NEW	$518,787
														Subtotal = $518,787

Grand Total All Awards = $1,054,800

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Effects of TDP-43 Proteinopathy on Retrotransposon Activation and Cell-Type Specific Vulnerability in a Mammalian Model of Alzheimer's and Related Dementias

Award Number: R01AG079898

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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