Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models
Jie Jiao,
Ge Gao,
Junge Zhu,
Chaodong Wang,
Lei Liu,
Hui Yang
Affiliations
Jie Jiao
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Key Laboratory on Parkinson's Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Beijing, China
Ge Gao
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Key Laboratory on Parkinson's Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Beijing, China
Junge Zhu
Department of Neurology & Neurobiology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
Chaodong Wang
Department of Neurology & Neurobiology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China; Corresponding author.
Lei Liu
Department of Biochemistry and Molecular Biology, Capital Medical University, School of Basic Medicine, Beijing, China; Corresponding author.
Hui Yang
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Key Laboratory on Parkinson's Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Beijing, China; Corresponding author.
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.
