Recent findings from a preclinical study conducted by Weill Cornell Medicine researchers have uncovered a pivotal role of the enzyme PGK1 in brain cell energy production, offering new hope for Parkinson’s disease treatment. The study reveals that enhancing PGK1 activity could counteract the energy deficits in dopamine neurons, which are critically involved in Parkinson’s disease, potentially slowing or even halting the disease’s progression.
The study is published in Science Advances in an article titled, “Phosphoglycerate kinase is a central leverage point in Parkinson’s disease–driven neuronal metabolic deficits.”
“Although certain drivers of familial Parkinson’s disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear,” the researchers wrote. “Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5′-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics.”
The study focused on PGK1, a “rate-limiting” enzyme essential for energy production in the axons of dopamine-producing neurons, which are severely affected in Parkinson’s disease. Researchers demonstrated that even a modest increase in PGK1 activity could restore neuronal energy levels under low-glucose conditions, preventing axonal degeneration in an animal model of Parkinson’s. The study also uncovered a surprising partnership between PGK1 and DJ-1, a protein known to be involved in Parkinson’s, highlighting a previously unknown energy-supporting role of DJ-1. These findings suggest that targeting PGK1 with more potent and selective drugs than those currently available, like terazosin, could offer a novel therapeutic approach to Parkinson’s disease.
“Our findings show that PGK1 can really make a big difference in Parkinson’s disease, in ways we didn’t anticipate,” said study senior author Timothy Ryan, PhD, the Tri-Institutional Professor of Biochemistry at Weill Cornell Medicine. “I’m very optimistic that this line of research has the potential to generate new Parkinson’s treatments.”
The new focus on PGK1 originated from recent studies showing that the FDA-approved drug terazosin, which is used to treat prostate enlargement, also happens to enhance PGK1’s energy-production activity and has beneficial effects in multiple animal models of Parkinson’s. In these studies, however, terazosin’s ability to boost PGK1 activity was quite weak, leaving uncertainty over its mechanism of action. Further evidence of the drug’s proposed role in boosting neural protection came from a retrospective study in humans showing that terazosin significantly reduced the risk of developing Parkinson’s.
“Pharma companies have been skeptical that this weak enhancement of PGK1 can explain these benefits in Parkinson’s models,” said Ryan.
Ryan’s team helped resolve this issue with sensitive assays that elucidated PGK1’s role as an energy producer in neurons. This role, the researchers showed, is so important that even a small boost to PGK1 activity, such as terazosin provides, is enough to keep axons functioning when levels of glucose, which PGK1 helps convert to basic units of chemical energy, are low. The experiments included low-glucose situations caused by known Parkinson’s-linked gene mutations.
The team also made a surprising discovery concerning a protein called DJ-1, whose impairment through mutation is another known genetic cause of Parkinson’s. DJ-1 is a “chaperone” that is thought to protect neurons by preventing harmful protein aggregation. However, the team found that DJ-1 works in an unexpected energy-supplying role as a close partner of PGK1—and indeed is necessary for the benefits of PGK1 enhancement.
Ryan noted the results add weight to the theory that an energy supply deficit in the most vulnerable dopamine neurons—due to aging, genetic, and environmental factors—is a general early driver of Parkinson’s, and that moderately enhancing the activity of just one enzyme, PGK1, may be enough to reverse this deficit and block the disease process.
“Now I can say I’m confident that this enzyme is what should be targeted,” Ryan added. “Given the positive impact of terazosin in protecting against Parkinson’s in humans, and the fact that this drug was never optimized for PGK1 enhancement, it is exciting to consider the possible clinical impact of new drugs that, compared with terazosin, can enhance PGK1 activity more potently and selectively.”
This research underscores the critical importance of PGK1 in maintaining neuronal energy supply, particularly in the vulnerable dopamine neurons impacted by Parkinson’s disease. By focusing on this enzyme, scientists may have unlocked a new pathway to potentially more effective treatments for Parkinson’s, offering hope to millions of people affected by this debilitating condition. As research progresses, the development of drugs specifically designed to enhance PGK1 activity could mark a significant step forward in the fight against neurodegenerative diseases.
