Knockdown of RNF128 attenuated Parkinson's-induced mitochondrial dysfunction in neurons by stabilizing the SIRT1 protein

Mitochondrial dysfunction is closely related to the pathogenesis of Parkinson’s disease (PD). Studies have shown that ubiquitination plays a crucial role in regulating mitochondrial dysfunction. As a ubiquitin Ligase, RNF128 may influence mitochondrial function by modulating its ubiquitination activity. This study aimed to investigate the specific effect and mechanism of RNF128 on PD-induced mitochondrial dysfunction in neurons. Animal and cellular models of PD were established for experimental investigation by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and treatment of SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). Motor function was evaluated via the rotarod test and pole climbing test; pathological brain tissue damage was detected via H&E staining; mitochondrial function was detected via MitoSOX Red staining, JC-1 staining, and ATP content determination. The binding of RNF128 and SIRT1 was detected via coimmunoprecipitation, and the expression levels of related proteins were detected via Western blotting and immunofluorescence. The result shows that RNF128 is highly expressed in PD. Knocking down RNF128 improves MPTP-induced motor dysfunction, increases the number of TH-positive neurons, and attenuates brain tissue damage in PD mice. At the cellular level, knocking down RNF128 led to reduced mitochondrial ROS levels and increased mitochondrial membrane potential and ATP levels, thereby ameliorating MPP+-induced mitochondrial dysfunction in neuronal cells. In terms of molecular mechanisms, the expression of SIRT1 is downregulated in PD, and RNF128 interacts with SIRT1 to increase the ubiquitination and degradation of SIRT1. Knocking down SIRT1 partially reverses the improvement in mitochondrial function achieved by knocking down RNF128. Overall, knocking down RNF128 improves mitochondrial dysfunction by increasing SIRT1 expression, thereby alleviating neuronal injury in PD.

Mitochondrial function; Neurons; Parkinson’s disease; RNF128; SIRT1.