Energy-Producing Enzyme Fuels the Brain with Promise for Treating Parkinson’s Disease (original) (raw)

Posted on September 12th, 2024 by Dr. Monica M. Bertagnolli

Credit: Donny Bliss/NIH

In Parkinson’s disease, neurons in parts of the brain gradually weaken and die, leading people to experience worsening problems with movement and other symptoms. While the causes of this disease aren’t fully known, studies have suggested the Parkinson’s brain lacks fuel to power dopamine-producing neurons that are essential for movement. When too many of those neurons are lost, Parkinson’s disease symptoms appear. But what if there was a way to boost energy levels in the brain and stop the neurodegenerative process in its tracks?

While the findings are preliminary, an NIH-supported study reported in Science Advances takes an encouraging step toward this goal. The key element, according to the new work, is an energy-producing enzyme known as phosphoglycerate kinase (PGK1). In fact, these latest preclinical findings in models of the disease suggest that boosting this enzyme in the brain even slightly may be enough to restore energy and afford some protection against Parkinson’s disease.

The team, led by Timothy Ryan and Alexandros Kokotos, Weill Cornell Medicine, New York City, was inspired by recent discoveries suggesting an unexpectedly important role for PGK1 in protecting the normal function of neurons. They knew PGK1 plays an essential role in the pathway through which cells use glucose to generate and store energy in the form of adenosine 5′-triphosphate (ATP) molecules. The surprise came when studies showed the drug terazosin, which is used to treat high blood pressure and enlarged prostate, has an unexpected side effect: it enhances PGK1 activity, although perhaps weakly.

Could the boost in PGK1 activity be enough to fuel and protect dopamine-producing neurons? Studies in Parkinson’s models including mice, rats, flies, and human cells treated with terazosin suggested that it could. A retrospective study in people taking terazosin for an enlarged prostate also showed that those taking the drug were less likely to develop Parkinson’s.

As promising as that sounded, it was hard to imagine that such a seemingly small increase in PGK1 activity was enough to explain the findings. To investigate further in the new study, the researchers ran more sensitive studies to see just how much of a difference PGK1 can make when it comes to energy production in neurons. Their new studies show that even a small increase in PGK1 activity keeps neurons firing, even when glucose levels are low.

The researchers report that the increases in PGK1 they saw were enough to protect neurons carrying mutations in genes with known links to familial forms of Parkinson’s disease. They found that effects of a PGK1 boost also depend on another protein, called DJ-1, which has also been implicated in Parkinson’s disease. When the researchers experimentally increased PGK1 levels in mouse models of the disease, it strongly protected their dopamine neurons.

For the approximately one million Americans with Parkinson’s disease today, current treatments help to relieve symptoms but don’t stop the disease from progressing. These new findings raise the possibility that terazosin or drugs that enhance PGK1 activity even more may fuel the brain, helping to protect essential dopamine-producing neurons to treat or even prevent Parkinson’s disease, as well as other neurodegenerative conditions where PGK1 may play a role.

Reference:

Kokotos AC, et al. Phosphoglycerate kinase is a central leverage point in Parkinson’s Disease driven neuronal metabolic deficits. Science Advances. DOI: 10.1126/sciadv.adn6016 (2024).

NIH Support: National Institute of Neurological Disorders and Stroke, National Institute of General Medical Sciences