Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits

Abstract

Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We Carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is the rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction in-vivo and modest changes in PGK1 activity dramatically supressed hypometabolic dysfunction in-vitro. Furthermore, PGK1 is cross-regulated by PARK7(DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.

Differential Control of Inhibitory and Excitatory Nerve Terminal Function by Mitochondria

“…It is notable that despite the greater respiratory capacity in inhibitory axons, the dynamics of ATP changes during intense electrical stimulation in glucose were similar to those seen in excitatory axons (Figure 2A). Both the activity driven ATP deficit (Figure 2B) and recovery following stimulation (Supplementary Figure 1B) were similar in the two neuron classes, suggesting that acute ATP dynamics are governed largely by glycolysis, consistent with our recent discovery that the first ATP producing enzyme in glycolysis (phospoglycerate kinase 1) is rate limiting (Kokotos et al, 2023). The lack of a difference in excitatory and inhibitory ATP recovery rates following stimulation even in conditions of metabolic compromise (Supplementary Figure 1C, 1D, 1F) suggests that ATP consumption and production rates during and directly following stimulation are similarly well equipped to meet metabolic need in excitatory and inhibitory neurons.…”

Characterization of β-Hydroxybutyrate as a Cell Autonomous Fuel for Active Excitatory and Inhibitory Neurons

“…In a second approach, we used a synaptic endurance assay that we recently developed where neurons are subjected to repeated rounds of stimulation at minute intervals ( Kokotos et al, 2023 ). We previously showed that under sufficient glycolytic fuel conditions, excitatory neurons are capable of sustaining at least ten rounds of stimulation without a significant slowing of SV recycling ( Kokotos et al, 2023 ). Here, we found that both excitatory and inhibitory neurons can sustain synaptic function under this paradigm when fueled by either lactate and pyruvate or BHB ( Figure 3A , 3B ).…”

Insights from Single-Cell RNA-seq: Identifying the Actin Gene Family as Novel Drivers in Parkinson’s Disease

“…Regarding the downregulated gene, MDMA promotes MALAT1 expression and inhibits the targeted downregulation of MEKK3 by miR-124, resulting in upregulation of the expression of MEKK3 and finally jointly promoting PD progression (24). In PD induced neuronal metabolic deficits, phosphoglycerate kinase (PGK1) serves as a crucial focal point (25). Moreover, it has been shown that inhibition of prolyl hydroxylase is a promising therapeutic strategy for PD through improving the mitochondrial function under oxidative stress (26).…”