Upregulated hexokinase 2 expression induces the apoptosis of dopaminergic neurons by promoting lactate production in Parkinson's disease

Parkinson's disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Aerobic glycolysis and lactate production have been shown to be upregulated in dopaminergic neurons to sustain ATP levels, but the effect of upregulated glycolysis on dopaminergic neurons remains unknown. Since lactate promotes Apoptosis and α-synuclein accumulation in neurons, we hypothesized that the lactate produced upon upregulated glycolysis is involved in the Apoptosis of dopaminergic neurons in PD. In this study, we examined the expression of Hexokinase 2 (HK2) and Lactate Dehydrogenase (LDH), the key Enzymes in glycolysis, and lactate levels in the substantia nigra pars compacta (SNpc) of a MPTP-induced mouse model of PD and in MPP⁺-treated SH-SY5Y cells. We found that the expression of HK2 and LDHA and the lactate levels were markedly increased in the SNpc of MPTP-treated mice and in MPP⁺-treated SH-SY5Y cells. Exogenous lactate treatment led to the Apoptosis of SH-SY5Y cells. Intriguingly, lactate production and the Apoptosis of dopaminergic neurons were suppressed by the application of 3-bromopyruvic acid (3-Brpa), a HK2 inhibitor, or siRNA both in vivo and in vitro. 3-Brpa treatment markedly improved the motor behaviour of MPTP-treated mice in pole test and rotarod test. Mechanistically, lactate increases the activity of adenosine monophosphate-activated protein kinase (AMPK) and suppresses the phosphorylation of serine/threonine kinase 1 (Akt) and mammalian target of rapamycin (mTOR). Together, our data suggest that upregulated HK2 and LDHA and increased lactate levels prompt the Apoptosis of dopaminergic neurons in PD. Inhibition of HK2 expression attenuated the Apoptosis of dopaminergic neurons by downregulating lactate production and AMPK/Akt/mTOR pathway in PD.