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Mitochondrial Sirtuin 3 in Parkinson's disease

Award Number: R01NS110085
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Mitochondrial Sirtuin 3 in Parkinson's disease - The overall aim of this application is to investigate mechanisms of alpha-synuclein (αsyn)-induced mitochondrial dysfunction in Lewy body diseases (LBD). Despite its predominant localization in the cytosol, αsyn localizes to mitochondria in post-mortem LBD brains. Within the mitochondria, αsyn accumulation can impair complex I and IV function, decrease membrane potential, increase levels of reactive oxygen species, and increase apoptosis associated with cytochrome c release from the mitochondria. Together these data suggest an increase in mitochondrial αsyn expression and/or abnormal accumulation of toxic aggregates interferes with mitochondrial function. Maintaining mitochondrial health is essential to prevent neuronal cell death in the brain. Sirtuin 3 (SIRT3) is a NAD+-dependent protein deacetylase exclusively localized to the mitochondria where it regulates mitochondrial processes including protein deacetylation, organelle biogenesis, and oxidative stress. SIRT3 is expressed at high levels in the brain and other nervous system tissues, and can act as a pro- survival factor, playing an essential role in protecting neurons under conditions of excitotoxicity and rescuing neuronal loss in neurodegenerative models. Experimental evidence indicates that SIRT3- induced neuroprotection against oxidative stress is partially mediated by enhancement of mitochondrial biogenesis and integrity. As we consider sirtuin-based drug therapies for diseases of ageing, it is important to determine if modulating SIRT3 can protect against neurodegeneration where mitochondrial dysfunction has been demonstrated to play a role. This proposal will investigate how mitochondrial SIRT3 contributes to αsyn-induced mitochondrial dysfunction in 3 coordinated aims. In aim 1 we will perform comprehensive mitochondrial function analyses to reveal how αsyn accumulation leads to mitochondrial damage and the role of SIRT3 therein using patient-derived cells and postmortem brain. In aim 2 we will interrogate the SIRT3 regulated acetylome to identify novel targets of αsyn-associated mitochondrial dysfunction, and in aim 3 we will validate SIRT3 as a novel target for therapeutic intervention in PD in a comprehensive in vivo approach using genetic overexpression and pharmacological activation. The proposed rigorous analysis of various mitochondrial aspects will dissect causes from consequences and reveal the cross-talk between αsyn, SIRT3, and mitochondrial signaling pathways as well as oxidative and protein stress responses.


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 = -$15,953 )
2026	2023	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/30/2026	NON-COMPETING CONTINUATION	-$15,953
														Subtotal = -$15,953

Issue Date FY: 2023 ( Subtotal = $476,492 )
2023	2023	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/18/2023	NON-COMPETING CONTINUATION	$476,492
2023	2022	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $476,492

Issue Date FY: 2022 ( Subtotal = $476,492 )
2022	2022	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/19/2022	NON-COMPETING CONTINUATION	$476,492
														Subtotal = $476,492

Issue Date FY: 2021 ( Subtotal = $546,851 )
2021	2021	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/24/2021	NON-COMPETING CONTINUATION	$476,492
2021	2021	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/28/2021	SUPPLEMENT FOR EXPANSION	$70,359
														Subtotal = $546,851

Issue Date FY: 2020 ( Subtotal = $476,492 )
2020	2020	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/8/2020	NON-COMPETING CONTINUATION	$476,492
														Subtotal = $476,492

Issue Date FY: 2019 ( Subtotal = $476,492 )
2019	2019	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/9/2019	NEW	$476,492
														Subtotal = $476,492

Grand Total All Awards = $2,436,866

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Mitochondrial Sirtuin 3 in Parkinson's disease

Award Number: R01NS110085

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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