Increasing PGK1 expression may help protect dopamine-producing neurons and provide valuable insights into potential therapeutic strategies for Parkinson's disease, according to a recent study.
Researchers identified phosphoglycerate kinase 1 (PGK1) as a key enzyme in addressing neuronal metabolic deficits associated with Parkinson's disease (PD). PGK1 serves as a rate-limiting enzyme in glycolysis, essential for adenosine triphosphate (ATP) production in neurons. The study, published in Science Advances, demonstrated that upregulating PGK1 expression may enhance ATP synthesis, which is critical for preserving synaptic function, particularly in neurons impacted by PD-related mutations, such as those involving PARK20/Synaptojanin 1.
Enhancing PGK1 expression led to a 14% decrease in ATP depletion during synaptic activity in low-glucose conditions, whereas control neurons experienced a 30% decrease. Overexpressing PGK1 also maintained synaptic function under low-glucose conditions (0.1 mM glucose) throughout all 10 rounds of activity that were tested.
In an in vivo model, PGK1 expression in the substantia nigra resulted in an approximately 2.5-fold increase in tyrosine hydroxylase-positive neurons compared to controls following a 6-OHDA injection, suggesting a protective effect on neurons.
Results of the study further elucidate the interplay between PGK1 and PARK7/DJ-1, a molecular chaperone implicated in PD. Loss of PARK7/DJ-1 disrupts neuronal ATP production, resulting in synaptic dysfunction. However, the study showed that increasing PGK1 expression protects striatal dopaminergic neurons, which are characteristically vulnerable in PD. This protective effect was demonstrated in both in vitro and in vivo models, indicating that PGK1 activity is crucial for maintaining neuronal energy homeostasis.
These findings suggest that targeting PGK1 may address the bioenergetic deficits contributing to PD pathogenesis.
Full disclosures can be found in the published study.