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Role of Ape1 in Huntington's Disease Neurodegeneration

Award Number: SC1NS095380
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: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 10/14/2020

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Role of Ape1 in Huntington's Disease Neurodegeneration - ABSTRACT Huntington’s disease (HD) is a devastating neurological disease to which no pharmacological interventions are yet available to cure the disease. HD is caused by a mutation in the huntingtin gene consisting of an expanded CAG repeat. We recently demonstrated a regulatory role of APE1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, on mitochondrial (mt) function. First, silencing APE1 caused reductions of mt respiratory capacity in mutant huntingtin (mhtt)-expressing mouse and human cells. Second, levels of APE1 in the mt decreased in mutant HD cells following an oxidative insult, suggesting that mutant htt may interfere with the mt import of APE1. These observations suggest a novel mechanism for APE1 on the maintenance of mt function in HD. APE1 not only exhibits DNA repair activity of endogenous and exogenous oxidative and alkylating damage via BER, but also functions as a reduction-oxidation (redox) co-activator of certain transcription factors involved in neuronal survival. Whether APE1 DNA repair function, its redox activity or both are essential for maintenance of mt function and APE1 mt localization in HD is not known. Thus, our main objective is to determine the mechanisms of APE1- mediated mt dysfunction in the context of mutant htt. This proposal will test the overall hypothesis that mhtt mediates mt dysfunction and neurodegeneration by targeting APE1. To test our hypothesis, we will determine what mechanism(s) might trigger APE1-associated mt dysfunction in the context of the htt mutation by determining if 1) Mutant htt affects the repair of mtDNA and mitochondrial function by preventing APE1 activity and localization into the mitochondria and 2) APE1 DNA repair or redox activity (or both) are essential for the maintenance of mt function. This study is likely to provide insight into a possible regulatory mechanism of Ape1 in mhtt-induced mt dysfunction and neurodegeneration.


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 = -$33,316 )
2026	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	000	4	10/1/2025	SUPPLEMENT FOR EXPANSION	-$33,316
														Subtotal = -$33,316

Issue Date FY: 2022 ( Subtotal = -$519 )
2022	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/14/2021	NON-COMPETING CONTINUATION	-$519
														Subtotal = -$519

Issue Date FY: 2021 ( Subtotal = -$6,505 )
2021	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	000	4	11/4/2020	SUPPLEMENT FOR EXPANSION	$0
2021	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	002	4	8/8/2021	SUPPLEMENT FOR EXPANSION	-$6,505
2021	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = -$6,505

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	9/14/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $320,451 )
2019	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	4	4/12/2019	SUPPLEMENT FOR EXPANSION	$320,451
2019	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/12/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $320,451

Issue Date FY: 2018 ( Subtotal = $325,791 )
2018	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/25/2018	NON-COMPETING CONTINUATION	$325,791
														Subtotal = $325,791

Issue Date FY: 2017 ( Subtotal = $295,744 )
2017	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/7/2017	NON-COMPETING CONTINUATION	$295,744
														Subtotal = $295,744

Issue Date FY: 2016 ( Subtotal = $339,541 )
2016	2016	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/12/2016	NON-COMPETING CONTINUATION	$339,541
														Subtotal = $339,541

Issue Date FY: 2015 ( Subtotal = $334,494 )
2015	2015	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/22/2015	NEW	$334,494
														Subtotal = $334,494

Grand Total All Awards = $1,575,681

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Role of Ape1 in Huntington's Disease Neurodegeneration

Award Number: SC1NS095380

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: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 10/14/2020

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