The critical role of PGK1 in Parkinson’s disease

An enzyme called PGK1 plays an unexpectedly crucial role in the production of chemical energy in brain cells, according to a preclinical study led by researchers at Weill Cornell Medicine. The researchers found that boosting activity can help the brain resist the energy deficits that can lead to Parkinson’s disease.

The study, published on August 21, 2024 in Scientific progresspresented evidence that PGK1 is a “rate-limiting” enzyme in energy production in the output signaling branches, or axons, of the dopamine neurons affected in Parkinson’s disease. This means that even a modest increase in PGK1 activity can have an outsized effect on restoring neuronal energy supply under low-fuel conditions; and the researchers showed that this could prevent the dysfunction and degeneration of axons normally seen in an animal model of Parkinson’s disease. .

Our findings show that PGK1 can really make a big difference in Parkinson’s disease, in ways we didn’t expect. I am very optimistic that this line of research has the potential to generate new Parkinson’s treatments.”

Dr. Timothy Ryan, senior study author and tri-institutional professor of biochemistry, Weill Cornell Medicine

The first author of the study was Dr. Alexandros Kokotos, a postdoctoral researcher in the Ryan Laboratory.

Parkinson’s affects approximately one million Americans and is the most common neurodegenerative disorder after Alzheimer’s disease. The disease affects key populations of dopamine-producing neurons, initially weakening and eventually killing their synapses or points of connection with other neurons. The resulting signs and symptoms of the disease include movement disorders, sleep problems and eventually dementia. Current treatments address the symptoms, but do not stop the progression of the disease.

For decades, several studies have pointed to failure of neuronal energy supply as a factor in Parkinson’s disease, a disease that affects neurons with very high energy demands. Yet researchers have not found a good energy-related target for disease treatments.

The new focus on PGK1 came from recent studies showing that the Food and Drug Administration-approved drug terazosin, used to treat prostate enlargement, also happens to improve the energy production activity of PGK1 and has beneficial effects in multiple animal models of Parkinson’s . However, in these studies, terazosin’s ability to stimulate PGK1 activity was quite weak, leaving uncertainty about its mechanism of action. Further evidence of the drug’s proposed role in boosting neural protection came from a retrospective study in humans that found terazosin significantly reduced the risk of developing Parkinson’s disease.

“Pharma companies have been skeptical that this weak enhancement of PGK1 can explain these benefits in Parkinson’s models,” says Dr. Ryan, who is also a professor of biochemistry in anesthesiology at Weill Cornell Medicine.

In the new study, Dr.’s team helped. Ryan to solve this problem with sensitive assays that clarified the role of PGK1 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, is enough to keep the axons functioning when the levels of glucose, which PGK1 helps convert into basic units of chemical energy, be low. The experiments included low glucose situations caused by known Parkinson’s-linked gene mutations.

The team also made a surprising discovery involving a protein called DJ-1, whose mutational damage is another known genetic cause of Parkinson’s. DJ-1 is a ‘chaperone’ thought to protect neurons by preventing harmful protein aggregation. However, the team found that DJ-1 serves an unexpected energy-providing role as a close partner of PGK1, and is indeed necessary for the benefits of PGK1 enhancement.

For Dr. Ryan, the results add weight to the theory that a lack of energy supply in the most vulnerable dopamine neurons – due to aging, genetic and environmental factors – is a common early cause of Parkinson’s disease, and that a moderate increase in activity of just one enzyme, PGK1, may be enough to reverse this deficiency and block the disease process.

“Now I can say that I am confident that this enzyme is the target,” said Dr. Ryan. “Given the positive impact of terazosin in protecting against Parkinson’s disease in humans, and the fact that this drug has never been optimized for enhancement of PGK1, it is exciting to consider the potential clinical impact of new drugs that, compared to terazosin , could improve PGK1 activity even more.” powerful and selective.”