Abstract
Oxidized protein overloading caused by diabetes is one accelerating pathological pathway in diabetic encephalopathy development. To determine whether the PA28-regulated function of the proteasome plays a role in diabetes-induced oxidative damaged protein degradation, brain PA28α and PA28β interference experiments were performed in a high-fat diet (HFD) and streptozotocin (STZ)-induced rat model. The present results showed that proteasome activity was changed in the brains of diabetic rats, but the constitutive subunits were not. In vivo PA28α and PA28β inhibition via adeno-associated virus (AAV) shRNA infection successfully decreased PA28 protein levels and further exacerbated oxidized proteins load by regulating proteasome catalytic activity. These findings suggest that the proteasome plays a role in the elimination of oxidized proteins and that PA28 is functionally involved in the regulation of proteasome activity in vivo. This study suggests that abnormal protein turbulence occurring in the diabetic brain could be explained by the proteasome-mediated degradation pathway. Changes in proteasome activity regulator PA28 could be a reason to induce oxidative aggregation in diabetic brain.
Graphical Abstract
Proteasome regulator PA28 inhibition in vivo by AAV vector injection could aggravate oxidized proteins abundance in brain of HFD-STZ diabetic rat model.
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Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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This work was supported by the National Natural Science Foundation of China (NSFC) No.81760236 and No.81541116 to Zhao Bei.
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WDG was involved in major biochemistry experiment and manuscript writing. GH: work in diabetic rat model establishment. WYN and ZY: work in data collection and analysis. ZB contributed to research design and all results summary.
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We declare that animal experiments were carried out in accordance with the National Institutes of Health guide for the care and use of laboratory animals. The animal experiment protocol was examined and approved by the animal ethics committee of Dali University.
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Wu, Dg., Wang, Yn., Zhou, Y. et al. Inhibition of the Proteasome Regulator PA28 Aggravates Oxidized Protein Overload in the Diabetic Rat Brain. Cell Mol Neurobiol 43, 2857–2869 (2023). https://doi.org/10.1007/s10571-023-01322-y
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DOI: https://doi.org/10.1007/s10571-023-01322-y