An integrated analysis revealing that Sirt1-mediated decreased autophagy in the hippocampus of animal models of depression.

Abstract

BACKGROUND: Depression is a complex and prevalent mental disorder. Numerous studies have reported there were significant metabolomic and proteomic changes in hippocampus of depressed patients. However, few researches have systematically integrated these two omics data to identify key molecular mechanisms underlying depression. METHODS: Based on the data of Protein and Metabolite Network of Depression Database (ProMENDA), we integrate the significantly altered metabolites and proteins of hippocampus in animal models of depression. Pathway analysis was performed using IPA software to explore biological functional disturbance underlying these molecules. Finally, animal model construction, molecular biology experiments, and lentiviral transfection in vitro for gene knockout were performed to verify potential pathways. RESULTS: A total of 682 altered metabolites and 2300 altered proteins were retrieved. Pathway enrichment analysis identified 394 significantly enriched pathways, with the sirtuin signaling mediated autophagy being of particular interest. Further biological validations revealed the decrease of Sirt1, the autophagy-related genes, and autophagy markers in hippocampus of both mouse and Macaca fascicularis models of depression. Lastly, Sirt1 knockdown in primary neurons inhibited autophagy. CONCLUSION: This study expanded our understanding of multi-omics alterations in the hippocampus of depression by revealing that Sirt1 may mediate neuronal autophagy in the hippocampus of animal models of depression, which could further contribute to the pathophysiology of depression.