A groundbreaking study revealed that boosting the enzyme PGK1 can protect neurons from energy deficits that lead to Parkinson’s disease, promising new paths for treatment.
An enzyme called PGK1 has been identified as a crucial player in producing chemical energy within brain cells, as indicated by a preclinical study spearheaded by the robust research team at Weill Cornell Medicine. This discovery introduces new hopeful avenues for resisting the energy deficits that frequently culminate in Parkinson’s disease.
Published in Science Advances, the findings suggest that PGK1 is a “rate-limiting” enzyme in energy generation in the axons of dopamine neurons, which are notably impacted by Parkinson’s.
“Our findings show that PGK1 can really make a big difference in Parkinson’s disease, in ways we didn’t anticipate,” Timothy Ryan, the senior author of the study, said in a news release.
Ryan, who is the Tri-Institutional Professor of Biochemistry and a professor of biochemistry in anesthesiology at Weill Cornell Medicine, is optimistic about the potential for new treatments stemming from this research.
“I’m very optimistic that this line of research has the potential to generate new Parkinson’s treatments,” he added.
Parkinson’s affects around 1 million Americans and stands as the second most prevalent neurodegenerative disorder following Alzheimer’s. The disease principally targets dopamine-producing neurons, gradually weakening their synapses and ultimately leading to neuronal death. The resulting symptoms include movement disorders, sleep disturbances and progressive dementia. Although current therapies manage symptoms, none can halt the disease’s progression.
For years, researchers have suspected that disruptions in neuronal energy supply play a role in Parkinson’s, given the high energy needs of the affected neurons. However, until now, an effective energy-related target for treatments has remained elusive.
Intriguingly, the spotlight on PGK1 emerged from earlier studies showing that the FDA-approved drug terazosin, used to treat prostate conditions, also enhances PGK1’s energy-production capabilities. This drug had shown beneficial effects in various animal models of Parkinson’s, yet its mechanism wasn’t fully understood. A retrospective human study also indicated that terazosin substantially reduces the risk of developing Parkinson’s, bolstering its potential.
Despite this, skepticism lingered among pharmaceutical companies.
“Pharma companies have been skeptical that this weak enhancement of PGK1 can explain these benefits in Parkinson’s models,” added Ryan.
The new study, led by Ryan’s team, utilized sensitive assays to decode PGK1’s vital role as an energy producer in neurons. Their research revealed that even minimal PGK1 activity enhancement could maintain axonal functionality, especially under low-glucose conditions linked to known Parkinson’s gene mutations. This underlines PGK1’s profound impact in mitigating energy deficits.
Moreover, the team unearthed a novel role for the protein DJ-1, known for its protective function against harmful protein aggregation in neurons. Surprisingly, DJ-1 also acts in tandem with PGK1, providing essential support for PGK1’s energy-supplying roles. This revelation underscores the complexity and potential of targeting PGK1 in Parkinson’s treatment.