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Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity

Award Number: R35GM131781
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Research into the proteins that cause neurodegenerative diseases is undergoing a remarkable transformation with the detailed identification of biochemical and biophysical pathways that drive neuron stress and dysfunction. This MIRA project focuses on the cellular prion protein (PrPC), a ubiquitous glycoprotein protein of the central nervous system and peripheral tissues. Misfolding of PrPC to its scrapie form, PrPSc, causes a range of diseases including Creutzfeldt-Jakob disease (CJD), Fatal Familial Insomnia and Kuru. In addition, PrPC is now identified as a primary receptor for Aβ peptide oligomers that drive cytotoxicity in Alzheimer’s disease. PrPC is a Cu2+/Zn2+-binding protein that controls the anatomical distribution of these essential metal ions in the brain. Our program, initially supported by grant R01 GM065790, elucidated the coordination features of the metal ion binding sites, evaluated the detailed binding thermodynamics, and developed new concepts for understanding inherited prion diseases. Discoveries supported by this current MIRA grant find that copper and zinc promote an inter- domain interaction in PrPC that regulates neurotoxicity, pointing to fundamentally new molecular mechanisms of neurodegeneration. With immediate relevance to Alzheimer’s disease, we further showed that PrPC transports monomeric Aβ to the cell interior through endocytosis. We also developed a method for artificially glycosylating uniformly 15N-labeled PrPC and new results show that glycans exhibit surprising control over PrPC structure. The stage is now set for us to move in four critical directions, all with broad and profound relevance towards understanding the molecular processes that lead to neurodegeneration and dementia. First, we will elucidate the specific interactions between disease relevant forms of Aβ and their PrPC binding surfaces, with particular emphasis on the unexplored role of copper. Second, we plan to use the new method of microenvironment mapping to clearly identify membrane proteins adjacent to PrPC on the cell surface. Third, we will develop biophysical approaches geared towards understanding how PrPC disrupts membrane structure and compromises transmembrane voltages. Finally, we will apply methods learned from our research on the cystinosin transporter to interrogate the structure and mechanism of the Mitochondrial Pyruvate Carrier (MPC), recently implicated in AD.


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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	6	11/21/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $748,012 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	001	6	4/1/2024	COMPETING CONTINUATION	$506,759
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	002	6	8/30/2024	SUPPLEMENT FOR EXPANSION	$241,253
2024	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	5	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $748,012

Issue Date FY: 2023 ( Subtotal = $342,635 )
2023	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	5	4/20/2023	NON-COMPETING CONTINUATION	$342,635
														Subtotal = $342,635

Issue Date FY: 2022 ( Subtotal = $342,635 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	4	4/22/2022	NON-COMPETING CONTINUATION	$342,635
														Subtotal = $342,635

Issue Date FY: 2021 ( Subtotal = $342,635 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	3	4/22/2021	NON-COMPETING CONTINUATION	$342,635
														Subtotal = $342,635

Issue Date FY: 2020 ( Subtotal = $342,635 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	2	4/15/2020	NON-COMPETING CONTINUATION	$342,635
														Subtotal = $342,635

Issue Date FY: 2019 ( Subtotal = $684,511 )
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	001	1	8/20/2019	SUPPLEMENT FOR EXPANSION	$250,000
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	1	4/12/2019	NEW	$434,511
														Subtotal = $684,511

Grand Total All Awards = $2,803,063

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Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity

Award Number: R35GM131781

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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