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Role of heparan sulfate in neural cell vulnerability to prions

Award Number: R00AG061251
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Role of heparan sulfate in neural cell vulnerability to prions - PROJECT SUMMARY / ABSTRACT A major unresolved question in neurodegenerative disease is the mechanisms that drive selective cell vulnerability. Heparan sulfate proteoglycans (HSPGs) are glycoproteins that promote oligomerization of amyloid- β and prions in vitro and slow the clearance of amyloid-β in the brain of an Alzheimer’s disease mouse model. HSPGs interact with misfolded proteins through their HS chains and promote their internalization in immortalized neural cells. This protein aggregate uptake is profoundly impacted by the HS length and level of sulfation which, importantly, broadly differ between cell types. We and others have used highly sulfated HS-like glycopolymers to test the crucial role of HS in the interaction and in vitro replication of prions. However, the composition of endogenous HS and their specific roles in healthy aged and disease-affected brain are unknown. I found that mice expressing shorter HS chains showed prolonged survival and profoundly altered prion plaque distribution in brain when infected with a plaque-forming prion strain, but did not show any change in the prion disease phenotype caused by aggregate-forming prions. Here I will define the HS molecules that bind to physiological and misfolded prion protein in different neuronal populations. I hypothesize that the interaction of HS with misfolded prions is a major determinant underlying the selective cell vulnerability in prion disease. In Aim 1, I will determine the role of HS sulfation in the prion replication i) in vitro, using HS isolated from distinct neuronal populations, and ii) in vivo, by mouse models deficient in HS sulfation. I will measure how the variation in the HS sulfation impacts the PrP cell tropism and lesion targets in the brain, and how age affects HS composition. I will next manipulate the HS composition in different neuronal populations i) to measure the selective cell uptake of prions strains and their degree of dependence on HS (Aim 2), and ii) to test a new strategy to block prion progression based on using HSPG mimetics as vehicles to promote prion degradation in lysosomes (Aim 3). I expect to define the molecular mechanisms underlying selective cell vulnerability in prion disease and to discover new targets for the rational design of neuroprotective therapies for patients with prion disease. Due to the many commonalities between the pathogenesis of prion disease and Alzheimer’s disease, I plan to ultimately extend my research strategy to the study of cell targeting by amyloid-β. This K99/R00 application is an ideal pathway to independence that is supported by an outstanding group of mentors and advisors, extensive training in highly innovative techniques, a world-class scientific environment, and clear departmental commitment.


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 = $0 )
2026	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	5	1/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $249,000 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	5	7/23/2024	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	4	7/20/2023	NON-COMPETING CONTINUATION	$249,000
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	3/24/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $249,000

Issue Date FY: 2022 ( Subtotal = $249,000 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	8/15/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $747,000

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Role of heparan sulfate in neural cell vulnerability to prions

Award Number: R00AG061251

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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