GBE1 alleviates MPTP-induced PD symptoms in mice by enhancing glycolysis and oxidative phosphorylation

Abstract

In Parkinson’s disease (PD), the disturbance of energy metabolism due to glucose metabolic reprogramming may be a critical factor contributing to neuronal degeneration and death. Glycolysis, as the core process of glucose metabolism, not only serves as a fundamental source of energy but also integrates various metabolic pathways. However, the precise role of alterations in glycolysis-related pathways in the progression of PD remains elusive. We compared and analysed datasets from human databases of patients with PD and healthy controls to identify differentially expressed genes associated with glycolysis. Using the least absolute shrinkage and selection operator regression method and multivariate logistic regression analysis, we identified glucan-branching enzyme 1 (GBE1) as the most confident glycolytic gene implicated in PD. We validated the low expression of GBE1 in 1 − methyl − 4 − phenyl − 1,2,3,6 – tetrahydropyridine (MPTP)-induced PD animal models. Stereotaxic injection-mediated overexpression of GBE1 in striatal neurons improved motor dysfunction in these animal models. In vitro experiments demonstrated that GBE1 promotes the expression of lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB), enhances cellular glycolytic flux, and thereby increases the viability of PC12 cells under MPP⁺ treatment. Additionally, GBE1 alleviates mitochondrial dysfunction and restores oxidative phosphorylation in PD. In summary, by integrating machine learning and bioinformatics approaches, we identified GBE1, a glycolysis-related gene with significant implications for PD, elucidating its crucial role in glucose metabolic reprogramming and identifying potential therapeutic targets for modulating glucose metabolism in PD.