Metabolic reprogramming and the role of the BCAT protein - implications for type 2 diabetes and Alzheimer's disease

Usmari Moraes, Marcela

Abstract

Introduction: Oxidative stress and impaired homeostasis are key features of type 2 diabetes mellitus, which is comorbid with Alzheimer’s disease. Dysregulation of the branched-chain aminotransferase protein, which is overexpressed in AD, is suggested to be involved in metabolic reprogramming, thus impacting on oxidative stress and protein misfolding and aggregation. However, the precise changes in cellular health resulting from BCAT dysregulation remain unclear.

Methods and Results: Using SH-SY5Y neuronal models and a combination of metabolomics, biochemical and molecular techniques, we showed that changes in the expression of BCATc affect metabolite load and impair enzymes of glycolysis therefore acting as a glycolytic regulator, with changes in its redox status shifting its binding abilities to enzymes of the TCA cycle and oxidative phosphorylation. In addition, BCATc dysregulation led to impairment of proteins of the antioxidant system and an increase in ROS generation, disruption of the autophagy pathway and increased expression of toxic protein aggregates such as amyloid β and hyperphosphorylated tau.

Conclusion: These results demonstrate that BCATc dysregulation leads to metabolic reprogramming and the redox environment of the cell has a key role in these outcomes. Although further studies are required to evaluate whether BCATc overexpression occurs as a result of chronic levels of branched-chain amino acids or otherwise, this study showed that its expression levels are key in the regulation of energy pathways. This in turn impacts on oxidative stress and clearance mechanisms such as autophagy, ultimately contributing to protein aggregation and cellular death as observed in AD.

• Thesis Type: Thesis
• Deposit Date: Sep 29, 2022
• Publicly Available Date: Apr 24, 2023
• Keywords: metabolism, bcat, alzheimers, diabetes
• Public URL: https://uwe-repository.worktribe.com/output/10013675
• Award Date: Apr 24, 2023