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Determination of pathogenetic mechanisms in cortex-specific Sucla2 deficiency as a model for mitochondrial encephalopathy

Award Number: R01NS126597
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: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Determination of pathogenetic mechanisms in cortex-specific Sucla2 deficiency as a model for mitochondrial encephalopathy - Abstract Mitochondrial encephalomyopathy with mitochondrial DNA (mtDNA) depletion is a class of mitochondrial disease that causes neurological dysfunction with intellectual and developmental disabilities and myopathy. Deficiency of ADP-specific succinyl-CoA synthetase (SCS), a component of the TCA cycle, is one of the causes of mitochondrial encephalomyopathy with mtDNA depletion. SCS is an important integration point of the TCA cycle, intersecting energy metabolism and posttranslational succinylation. Previous studies have demonstrated that embryonic mice homozygous for a constitutive mutant Sucla2 allele are embryonic lethal and exhibit ADP-specific SCS deficiency and mtDNA depletion with detrimental effects on energy metabolism. For this proposal, to generate adult Sucla2 deficient animals, a conditional knockout strategy of Sucla2 limited to the postnatal forebrain is employed. Initial investigations reveal that the mutant animals exhibit a defect in learning and memory and perturbations of energy metabolism and global protein succinylation in the cortex in the absence of mtDNA depletion. This proposal is based on the hypothesis that adult phenotypes of Sucla2 deficiency are caused by a combination of TCA cycle dysfunction and perturbations of global posttranslational succinylation. The Sucla2-forebrain knockout model will be analyzed by a targeted battery of behavioral assays designed to fully characterize different cognitive domains for deficits. To determine the potential differential effects of developmental timing of Sucla2 loss, a conditional knockout with prenatal onset of Sucla2 deficiency will also be generated and subjected to longitudinal broad behavioral and in vivo physiological screening, including basic motor, autonomic, sensory, and cognitive assays in both adolescent and adult stages. Cortex from the forebrain conditional knockout model will be analyzed for histopathological changes, metabolomic alterations, TCA and ETC enzyme activities, global posttranslational succinylation and mtDNA content. An innovative approach using integrated single nuclear (sn) RNA-seq and snATAC-seq to identify differential gene expression patterns and alterations in chromatin accessibility landscape in different cortical cell types defined by distinct expression clusters will be employed and the datasets used to inform histopathological and metabolomic analyses. These studies will provide insights into the pathogenic mechanisms of Sucla2/SCS deficiency and establish a preclinical model to explore and develop novel therapeutic approaches.


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 = $457,649 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/11/2026	NON-COMPETING CONTINUATION	$457,649
														Subtotal = $457,649

Issue Date FY: 2025 ( Subtotal = $519,842 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/7/2025	NON-COMPETING CONTINUATION	$519,842
														Subtotal = $519,842

Issue Date FY: 2024 ( Subtotal = $504,093 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/21/2024	NON-COMPETING CONTINUATION	$504,093
														Subtotal = $504,093

Issue Date FY: 2023 ( Subtotal = $540,555 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/27/2023	NON-COMPETING CONTINUATION	$540,555
														Subtotal = $540,555

Issue Date FY: 2022 ( Subtotal = $517,067 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/26/2022	NEW	$517,067
														Subtotal = $517,067

Grand Total All Awards = $2,539,206

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Determination of pathogenetic mechanisms in cortex-specific Sucla2 deficiency as a model for mitochondrial encephalopathy

Award Number: R01NS126597

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: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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