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Alleviating Mitochondrial Dysfunction in PERK-deficient Neurodegenerative Disease

Award Number: F30AG081061
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/20/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Alleviating Mitochondrial Dysfunction in PERK-deficient Neurodegenerative Disease - PROJECT SUMMARY Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are hallmarks of pathologic aging and are intricately linked in the onset and pathogenesis of etiologically-diverse neurodegenerative disorders including Alzheimer’s disease (AD) and related dementias (ADRDs). This has led to significant interest in understanding how cells regulate mitochondria in response to ER stress. Intriguingly, the ER stress-responsive kinase PERK is localized to ER-mitochondria contact sites where it acts as an effector of both the unfolded protein response (UPR) and the integrated stress response (ISR). Additionally, PERK-dependent transcriptional and translational signaling modulates nearly all aspects of mitochondrial biology including remodeling of mitochondrial cristae and respiratory complexes to enhance energy capacity, regulation of mitochondrial proteostasis (i.e., protein import, chaperone activity, and proteolysis), and remodeling of membrane phospholipid composition to induce protective mitochondrial elongation. Through these mechanisms PERK protects mitochondria during ER stress; however, persistent PERK activation induced by severe or chronic ER stress leads to apoptosis. Thus, PERK signaling both promotes adaptive mitochondrial remodeling and dictates cell fate in response to varying levels of cellular stress. The importance of PERK in regulating adaptation and survival is further supported by clinical, genetic, and pharmacologic evidence demonstrating that imbalanced PERK signaling contributes to the pathogenesis of etiologically-diverse neurodegenerative diseases. Hypomorphic variants in the gene that encodes PERK (EIF2AK3) predispose individuals to tauopathies such as progressive supranuclear palsy (PSP) and late-stage AD. In addition, exogenous PERK activation mitigates tau pathology in PSP, further indicating that protective PERK signaling is insufficient in the pathogenesis of this disease. Collectively, these observations establish PERK as a critical regulator of mitochondrial adaptation to cellular insult and suggest that imbalances in PERK signaling contribute to mitochondrial dysfunction implicated in neurodegenerative disease pathogenesis. Using cell culture models derived from patients expressing a hypomorphic PERK variant, I will show that deficiencies in PERK signaling impair mitochondria and contribute to neurodegenerative phenotypes such as tau pathology (Aim 1). Further, I will demonstrate that pharmacologic activation of the ISR—a stress-responsive program comprised of the eIF2α kinases GCN2, HRI, PKR, and PERK—mitigates mitochondrial dysfunction and improves neuronal survival in a human neuronal model of PERK-deficient neurodegeneration (Aim 2). These efforts are significant as they will define a critical role for PERK in regulating mitochondrial adaptation during neurodegeneration and establish pharmacologic ISR activation as a potential therapeutic strategy against neurodegenerative disease—for which no disease-modifying treatments are currently available.


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 = -$25,738 )
2026	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	1/27/2026	NON-COMPETING CONTINUATION	-$25,738
														Subtotal = -$25,738

Issue Date FY: 2025 ( Subtotal = $36,538 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	3	7/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$36,538
2025	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	7/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $36,538

Issue Date FY: 2024 ( Subtotal = $35,974 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	3/28/2024	NON-COMPETING CONTINUATION	$34,694
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	2	5/2/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $35,974

Issue Date FY: 2023 ( Subtotal = $34,694 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	002	1	9/14/2023	NEW	$0
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	1	3/24/2023	NEW	$0
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	3/24/2023	NEW	$34,694
														Subtotal = $34,694

Grand Total All Awards = $81,468

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Alleviating Mitochondrial Dysfunction in PERK-deficient Neurodegenerative Disease

Award Number: F30AG081061

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/20/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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