Dataset Information

N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy.

ABSTRACT: Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explore the influence of NAT10-mediated mRNA acetylation on SAE and the mechanisms underlying cognitive dysfunction in this context. SAE was induced in C57BL/6 J male mice through cecal ligation and puncture (CLP) surgery. In vivo, we observed a significant increase in NAT10 expression in the excitatory neurons of the hippocampal the dentate gyrus (DG) in CLP mice, and this change was accompanied by a trend toward an increase in mRNA acetylation. Specific knockout of Nat10 in neurons led to an improvement in cognitive dysfunction in septic mice. Proteomic analysis and RNA immunoprecipitation and real-time quantitative polymerase chain reaction (RIP-qPCR) revealed GABABR1 as a crucial downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, subsequently weakening inhibitory postsynaptic currents in hippocampal DG neurons. Additionally, RNA sequencing (RNA-seq) revealed an increase in hippocampal inflammation post-CLP, characterized by the excessive activation of microglia and the release of inflammatory mediators. These factors were linked to the increased NAT10 expression in neurons. Treatment with PLX3397, a microglia depleting agent, resulted in a reduction in NAT10 and GABABR1 expression in neurons, which correlated with improvements in cognitive dysfunction induced by SAE. Taken together, our findings revealed that after CLP, NAT10 in neurons of the hippocampal DG region promotes GABABR1 expression by acetylating its mRNA, leading to cognitive dysfunction. These findings provide new insights into the molecular pathogenesis of SAE and suggest potential therapeutic targets for addressing cognitive deficits in septic patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE253309 | GEO | 2024/08/13

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Dysregulated cardiac function after sepsis is common in intensive care unit (ICU) and known to predict poor long-term outcome and increase mortality. Effective therapeutic strategies are largely lacking. Moreover, the pathological feature and the molecular mechanism underlying cardiac dysfunction induced by sepsis remain unclear. Here, by performing echocardiograms on rodents after induction of polymicrobial sepsis with cecum ligation and puncture (CLP), we assessed the temporal dynamics of left ventricular ejection fraction (LVEF) and a serial of hemodynamics parameters on animals at different time point after CLP. Intriguingly, the mean LVEF is comparable in mice induced by CLP and sham, whereas survivors post CLP had stable LVEF and non-survivors had markedly fluctuated LVEF at early phase of CLP induction, suggesting LVEF away from normal range is highly associated with mortality. Consistent with clinical observations of depressed, preserved or hyperdynamic LVEF in septic patients from data compiled using our ICU cohort and from other studies, CLP-induced mice fall into three groups based on LVEF measured at 24 hours after surgery: high LVEF (HEF, LVEF>=90%), low LVEF (LEF, LVEF<65%), and normal LVEF (NEF, 65%=<LVEF<90%). We performed genome-wide transcriptomic and proteomic profiling on left ventricle samples collected from three CLP groups and sham mice. By implementing pathway analysis, gene set enrichment and coexpression network analysis, we identified jointly and distinctively changed genes, proteins and biologically-essential processes and pathways in three CLP groups with different LVEF. Notably, transmission electron microscopy examination shows remarkable mitochondrial and sarcomere defects in three CLP groups with different phenotypes associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury, serving as a framework for future research into pathology and molecular mechanism of sepsis-induced cardiomyopathy.

Dataset Information

N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets