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Regulation of SORLA by beta-arrestin2

Award Number: R01AG067729
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Regulation of SORLA by beta-arrestin2 - The ultimate goal of this study is to advance our understanding of the complexity of Alzheimer’s disease (AD) pathophysiology and to provide invaluable preclinical information on new treatment strategies. Sporadic AD involves multiple genetic risk factors. One of the top genetic risk factors for AD is SORL1; association between genetic variants of SORL1 and late-onset AD has been repeatedly revealed in genome-wide association studies. Furthermore, nonsense and missense mutations of SORL1 cause autosomal dominant early-onset AD, supporting an etiological role of this gene in AD. SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which exhibits a protective role in AD pathogenesis through regulation of endocytic function and amyloid β (Aβ) metabolism. Despite its importance in AD pathogenesis, our knowledge of how SORLA is regulated by intracellular signaling molecules and the relevance of this regulation to AD is surprisingly scarce. In our preliminary studies, we identified a novel interaction between SORLA and βarrestin2 (βARR2), a multifunctional trafficking/signaling adaptor that is potentially involved in AD. Our preliminary data suggest that βARR2 disrupts retromer-mediated retrograde transport of SORLA and reduces SORLA stability. Furthermore, we found a significant increase in the SORLA-βARR2 interaction, which correlates with a decrease in the SORLA-retromer interaction, in postmortem brain tissues of AD subjects when compared to controls. Therefore, we discovered a novel βARR2-dependent regulation of SORLA trafficking and stability that is relevant to AD. In this proposal, we will determine the pathophysiological significance and underlying mechanism of this novel regulation and use preclinical tests to explore its potential as a therapeutic target for AD. In Aim 1, we will determine how βARR2 alters SORLA trafficking and stability to disrupt the endosome network and Aβ metabolism. In Aim 2, we will test how this βARR2-dependent regulation of SORLA is modulated by intracellular signaling. In Aim 3, we will explore the therapeutic potential of targeting this novel regulatory pathway in ameliorating AD-related deficits using animal models.


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: 2026 ( Subtotal = -$258,197 )
2026	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	3	10/1/2025	EXTENSION WITH OR WITHOUT FUNDS	-$2,998
2026	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	3	10/1/2025	EXTENSION WITH OR WITHOUT FUNDS	-$255,199
														Subtotal = -$258,197

Issue Date FY: 2025 ( Subtotal = $759,881 )
2025	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	3	3/6/2025	EXTENSION WITH OR WITHOUT FUNDS	$759,881
														Subtotal = $759,881

Issue Date FY: 2024 ( Subtotal = $529,065 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	3	7/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$529,065
														Subtotal = $529,065

Grand Total All Awards = $1,030,749

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Regulation of SORLA by beta-arrestin2

Award Number: R01AG067729

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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