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Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE208692 | GEO | 2022/07/27

REPOSITORIES: GEO

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Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (RNA-Seq)

Project description:Lysine-succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the TCA cycle. Deficiency of succinyl-CoA synthetase (SCS), the TCA-cycle enzyme catalyzing the reversible conversion of succinyl-CoA to succinate, leads to mitochondrial encephalomyopathy in humans and embryonic lethality in mice. This report presents a conditional forebrain-specific knock-out (KO0 mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that the accumulation of succinyl-CoA in the absence of SCS leads to hyper-succinylation within the cerebral cortex of adult mice. With previous research identifying succinylation marks on histones, and with proteomic evidence of histone lysine-succinylation within the presented model, global chromatin accessibility was surveyed in Sucla2 mutant and control mice via ATAC-sequencing. Data show wide-scale alterations in chromatin landscape and global gene expression. Computational analysis of combined chromatin-accessibility and gene expression data reveal perturbation of neuronal transcriptional regulatory networks in the mutant forebrain, suggesting SCS-related changes in the protein succinylome and chromatin accessibility play a significant role in the neuronal pathogenesis of SCS-deficiency.

2022-07-27 | GSE208691 | GEO

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)

2022-07-27 | GSE208690 | GEO

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

Project description:Lysine-succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the TCA cycle. Deficiency of succinyl-CoA synthetase (SCS), the TCA-cycle enzyme catalyzing the reversible conversion of succinyl-CoA to succinate, leads to mitochondrial encephalomyopathy in humans and embryonic lethality in mice. This report presents a conditional forebrain-specific knock-out (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that the accumulation of succinyl-CoA in the absence of SCS leads to hyper-succinylation within the cerebral cortex of adult mice. Using immunoprecipitation (IP) and concomitant mass-spectrometry, a highly enriched succinylated proteome is identified in the Sucla2-deficient forebrain. The Sucla2-deficient changes in the succinylome are largely prevalent in metabolic pathways, including the TCA cycle and the electron transport chain (ETC). Specifically, increased succinylation of Complex I of the ETC correlates with functionally significant deficiency of the enzymatic complex. These results suggest that protein-succinylation plays a role in respiratory chain dysfunction associated with SCS-deficiency in patients.

2022-06-21 | MSV000089697 | MassIVE

Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.

Project description:Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.

| S-EPMC10683835 | biostudies-literature

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

Project description:Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

| PRJNA860613 | ENA

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)

Project description:Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)

| PRJNA860620 | ENA

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (RNA-Seq)

Project description:Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (RNA-Seq)

| PRJNA860619 | ENA

Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism.

Project description:Succinylation is a post-translational protein acylation modification that converts the cationic lysine side chain to an anion with large potential impacts on protein structure and function. Here we characterize the epigenome-wide distribution of succinyllysine marks in chromatin using chromatin immuno-precipitation sequencing (ChIP-seq). We estimate that more than one-third of all nucleosomes contain lysine succinylation marks and demonstrate a potential role of chromatin succinylation in modulating gene expression. We further demonstrate that defective tricarboxylic acid (TCA) cycle metabolism perturbs the succinyllysine distribution in chromatin, correlating with transcriptional responses. This is consistent with previous observations linking nucleosome succinylation with enhanced in vitro transcription. We additionally demonstrate that defective TCA cycle metabolism results in a DNA repair defect and sensitivity to genotoxic agents, consistent with previously reported chromatin hypersuccinylation effects observed in the context of SIRT7 depletion. Chromatin succinylation may thus represent a mechanism by which metabolism modulates both genome-wide transcription and DNA repair activities.

| S-EPMC5993049 | biostudies-literature

GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability.

Project description:Why certain diseases primarily affect one specific neuronal subtype rather than another is a puzzle whose solution underlies the development of specific therapies. Selective basal forebrain cholinergic (BFC) neurodegeneration participates in cognitive impairment in Alzheimer's disease (AD), yet the underlying mechanism remains elusive. Here, we report the first recapitulation of the selective BFC neuronal loss that is typical of human AD in a mouse model termed GAP. We created GAP mice by crossing Tg2576 mice that over-express the Swedish mutant human β-amyloid precursor protein gene with G protein-coupled receptor kinase-5 (GRK5) knockout mice. This doubly defective mouse displayed significant BFC neuronal loss at 18 months of age, which was not observed in either of the singly defective parent strains or in the wild type. Along with other supporting evidence, we propose that GRK5 deficiency selectively renders BFC neurons more vulnerable to degeneration.

| S-EPMC4872166 | biostudies-other

Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice.

Project description:Calcineurin (Cn), a phosphatase important for synaptic plasticity and neuronal development, has been implicated in the etiology and pathophysiology of neuropsychiatric disorders, including schizophrenia, intellectual disability, autism spectrum disorders, epilepsy, and Alzheimer's disease. Forebrain-specific conditional Cn knockout mice have been known to exhibit multiple behavioral phenotypes related to these disorders. In this study, we investigated whether Cn mutant mice show pseudo-immaturity of the dentate gyrus (iDG) in the hippocampus, which we have proposed as an endophenotype shared by these disorders. Expression of calbindin and GluA1, typical markers for mature DG granule cells (GCs), was decreased and that of doublecortin, calretinin, phospho-CREB, and dopamine D1 receptor (Drd1), markers for immature GC, was increased in Cn mutants. Phosphorylation of cAMP-dependent protein kinase (PKA) substrates (GluA1, ERK2, DARPP-32, PDE4) was increased and showed higher sensitivity to SKF81297, a Drd1-like agonist, in Cn mutants than in controls. While cAMP/PKA signaling is increased in the iDG of Cn mutants, chronic treatment with rolipram, a selective PDE4 inhibitor that increases intracellular cAMP, ameliorated the iDG phenotype significantly and nesting behavior deficits with nominal significance. Chronic rolipram administration also decreased the phosphorylation of CREB, but not the other four PKA substrates examined, in Cn mutants. These results suggest that Cn deficiency induces pseudo-immaturity of GCs and that cAMP signaling increases to compensate for this maturation abnormality. This study further supports the idea that iDG is an endophenotype shared by certain neuropsychiatric disorders.

| S-EPMC9682671 | biostudies-literature

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