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Protection from pathological tau by activation of the ER unfolded protein response

Award Number: R01AG066211
ORGANIZATION: NATIONAL INSTITUTE ON AGING
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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Protection from pathological tau by activation of the ER unfolded protein response - Pathological deposition of abnormal aggregated tau protein in neurons is one of the diagnostic hallmarks of Alzheimer's disease (AD) and related dementia (ADRD). How pathological tau causes dysfunction and degeneration of neurons remains an enigma. However, neuronal dysfunction and neurodegeneration clearly cause dementia. To understand how abnormal tau contributes to neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. In our previous work, we identified XBP-1, the master transcriptional regulator of the unfolded protein response (UPR), as a critical regulator of pathological tau accumulation and toxicity. ER stress and activation of the UPR have clearly been implicated in human tauopathy disorders by other laboratories although the functional consequences of UPR activation on tau pathology remain unclear. We have leveraged our C. elegans model of tauopathy to dissect the functional role of the UPR in tau pathology. We have found that tau pathology can induce ER stress, and that UPR activation protects against tauopathy through XBP-1s. We hypothesize that XBP-1s target genes can modulate accumulation and clearance of pathological tau. To test this hypothesis, we upregulated the UPR in neurons in the absence of ER stress, using a constitutively active XBP-1s expressing transgene. Transcriptomic studies of this system have revealed key XBP-1s target genes that modulate tauopathy and cross talk with other regulatory branches of the UPR (ATF6 and PERK branches). Given the high level of conservation of the UPR system between mammals and C. elegans, we propose to utilize the existing model and transgenes to dissect the mechanism by which the UPR protects against tau neurotoxicity. The Specific Aims of this project are to: 1) Identify the molecular mechanisms of XBP1s mediated suppression of tauopathy; 2) Examine UPR branch crosstalk contributing to tau clearance and ER associated degradation, 3) Address the disease relevance of XBP-1s target genes to neurodegeneration in both human disease and mouse models of tauopathy. Completion of the project as proposed will inform the molecular mechanisms by which the UPR participates in tauopathy. We will also explore the neuroprotective translational potential of XBP-1s mediated tau clearance in the mammalian brain.


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 = $567,765 )
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	5	1/8/2024	NON-COMPETING CONTINUATION	$510,988
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	001	5	6/10/2024	NON-COMPETING CONTINUATION	$56,777
														Subtotal = $567,765

Issue Date FY: 2023 ( Subtotal = $520,000 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	4	2/1/2023	NON-COMPETING CONTINUATION	$520,000
														Subtotal = $520,000

Issue Date FY: 2022 ( Subtotal = $520,000 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	3	1/14/2022	NON-COMPETING CONTINUATION	$468,000
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	001	3	5/10/2022	NON-COMPETING CONTINUATION	$52,000
														Subtotal = $520,000

Issue Date FY: 2021 ( Subtotal = $520,000 )
2021	2021	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	2	2/8/2021	NON-COMPETING CONTINUATION	$520,000
														Subtotal = $520,000

Issue Date FY: 2020 ( Subtotal = $530,011 )
2020	2020	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	1	1/14/2020	NEW	$530,011
														Subtotal = $530,011

Grand Total All Awards = $2,657,776

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Protection from pathological tau by activation of the ER unfolded protein response

Award Number: R01AG066211

ORGANIZATION: NATIONAL INSTITUTE ON AGING

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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