Work

Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models

Year: 2024

Type: article

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.

Source: Redox Biology

DOI: 10.1016/j.redox.2024.103399

Authors: Jie Jiao, Ge Gao, Junge Zhu, Chaodong Wang, Lei Liu, Hui Yang

Institutions: Capital Medical University, Beijing Institute for Brain Disorders, Xuan Wu Hospital of the Capital Medical University

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,900