The Critical Role of Enzyme PGK1 in Parkinson’s Disease
Parkinson’s disease is a neurodegenerative disorder that affects millions of people worldwide, causing movement impairments, sleep problems, and eventually dementia. Despite decades of research, there has been a lack of effective treatments that target the underlying cause of the disease. However, a recent preclinical study led by researchers at Weill Cornell Medicine has uncovered a potential new target for Parkinson’s therapy – an enzyme called PGK1.
In a study published in Science Advances, researchers demonstrated that PGK1 plays a critical role in the production of chemical energy in brain cells, specifically in the dopamine neurons affected by Parkinson’s disease. These neurons have high energy requirements, and a failure in energy production has long been suspected as a contributing factor to the development of the disease.
The researchers found that PGK1 is a “rate-limiting” enzyme in energy production in the axons of dopamine neurons. Even a modest increase in PGK1 activity can have a significant impact on restoring neuronal energy supply in low-fuel conditions. This, in turn, can prevent the dysfunction and degeneration of axons typically seen in Parkinson’s disease.
Dr. Timothy Ryan, the senior author of the study and a professor of Biochemistry at Weill Cornell Medicine, expressed optimism about the potential of targeting PGK1 for Parkinson’s treatment. He emphasized that boosting PGK1 activity could have a significant impact on the progression of the disease and may lead to the development of new therapies.
One intriguing finding from the study was the unexpected role of a protein called DJ-1, which is known to be involved in Parkinson’s disease. The researchers discovered that DJ-1 works in tandem with PGK1 to provide energy to neurons, and its impairment through mutation can contribute to the development of the disease. This revelation underscores the complex interplay of factors involved in Parkinson’s pathology.
The study also shed light on the potential therapeutic implications of the FDA-approved drug terazosin, which has been shown to enhance PGK1 activity and have beneficial effects in animal models of Parkinson’s. While the drug’s ability to boost PGK1 activity is modest, it has demonstrated promising results in protecting against the disease. This raises the possibility of developing new drugs that can more potently and selectively enhance PGK1 activity for improved clinical outcomes.
Overall, the study highlights the importance of understanding the role of energy metabolism in neurodegenerative diseases like Parkinson’s and the potential of targeting enzymes like PGK1 for therapeutic intervention. The findings open up new avenues for research and drug development aimed at addressing the underlying causes of Parkinson’s and improving patient outcomes.
The research described in this story was supported by grants from the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research.
