{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Jiao J"],"funding":["National Natural Science Foundation of China"],"pagination":["103399"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11533713"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["77"],"pubmed_abstract":["The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner-mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD."],"journal":["Redox biology"],"pubmed_title":["Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models."],"pmcid":["PMC11533713"],"funding_grant_id":["81870994","82371259"],"pubmed_authors":["Yang H","Zhu J","Liu L","Wang C","Gao G","Jiao J"],"additional_accession":[]},"is_claimable":false,"name":"Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models.","description":"The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner-mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Nov","modification":"2026-06-03T07:18:54.921Z","creation":"2025-04-06T09:35:42.778Z"},"accession":"S-EPMC11533713","cross_references":{"pubmed":["39427443"],"doi":["10.1016/j.redox.2024.103399"]}}