An enzyme known as PGK1 plays an unexpectedly vital role in generating chemical energy within brain cells, according to a recent preclinical study. Researchers discovered that increasing its activity might bolster the brain’s ability to counteract energy shortages that could trigger Parkinson’s disease.
An enzyme known as PGK1 plays an unexpectedly vital role in generating chemical energy within brain cells, according to a recent preclinical study conducted by Weill Cornell Medicine researchers. They found that enhancing its activity could help the brain combat energy shortages that may lead to Parkinson’s disease.
The study, released on August 21 in Science Advances, showed that PGK1 functions as a “rate-limiting” enzyme in energy production within the axons of dopamine neurons affected by Parkinson’s disease. This indicates that even a modest increase in PGK1 activity can significantly restore the energy supply in neurons under low-energy conditions. The research demonstrated that this enhancement could prevent the typical dysfunction and degeneration of axons seen in animal models of Parkinson’s disease.
“Our findings highlight that PGK1 can truly make a substantial difference in Parkinson’s disease, in ways we hadn’t expected,” said Dr. Timothy Ryan, the senior author and Tri-Institutional Professor of Biochemistry at Weill Cornell Medicine. “I’m quite hopeful that this research direction could lead to new therapies for Parkinson’s.”
The first author of the study was Dr. Alexandros Kokotos, a postdoctoral researcher in Dr. Ryan’s lab.
Parkinson’s disease affects approximately one million Americans and is the second most prevalent neurodegenerative disorder following Alzheimer’s. It specifically targets groups of dopamine-producing neurons, initially weakening their connections, or synapses, to other neurons, eventually leading to their death. Symptoms of the disease include movement difficulties, sleep disturbances, and, later on, dementia. Existing treatments focus on symptoms but do not halt the progression of the disease.
For many years, research has indicated that a decline in neuronal energy supply may contribute to Parkinson’s, particularly given that the disease impacts neurons with exceptionally high energy demands. Nonetheless, researchers have struggled to identify a suitable energy-related target for potential treatments.
The renewed interest in PGK1 stemmed from recent studies revealing that terazosin, a drug approved by the FDA for treating prostate enlargement, also boosts PGK1’s energy-producing capability and shows beneficial effects in various animal models of Parkinson’s. However, in these studies, the drug’s enhancement of PGK1 activity was relatively modest, leading to questions about its mechanism of action. Additional human studies suggested that terazosin significantly decreases the risk of developing Parkinson’s.
“Pharmaceutical companies have been doubtful that this slight boost in PGK1 could explain the observed benefits in Parkinson’s models,” stated Dr. Ryan, who is also a biochemistry professor in anesthesiology at Weill Cornell Medicine.
In their latest research, Dr. Ryan’s team addressed this uncertainty with precise assays that clarified PGK1’s role as an energy producer in neurons. Their findings indicated that even a small increase in PGK1 activity, such as that provided by terazosin, is sufficient to maintain axon function when glucose levels, which PGK1 helps convert into basic units of chemical energy, are low. The experiments included scenarios with reduced glucose levels due to known gene mutations linked to Parkinson’s.
The team made an unexpected discovery regarding a protein named DJ-1, whose mutation is another recognized genetic cause of Parkinson’s. DJ-1 acts as a “chaperone” believed to protect neurons from harmful protein accumulation. However, researchers uncovered that DJ-1 has an unforeseen role in energy supply, closely partnering with PGK1, and is essential for the benefits of enhancing PGK1 activity.
In Dr. Ryan’s view, the results support the idea that a lack of energy supply in the most vulnerable dopamine neurons—which can be impacted by aging, genetics, and environmental factors—may be a common early trigger of Parkinson’s. Therefore, moderately increasing the activity of PGK1 might reverse this energy deficit and stave off the progression of the disease.
“I’m now confident that targeting this enzyme is crucial,” Dr. Ryan expressed. “Given the favorable effects of terazosin in providing protection against Parkinson’s in humans and considering that this drug wasn’t specifically developed for enhancing PGK1, it’s exciting to think about the clinical benefits potential new drugs could have on PGK1 activity, more effectively than terazosin.”
This research was supported partially by the National Institute of Neurological Disorders and Stroke and the National Institute of General Medical Sciences, both part of the National Institutes of Health, through grant numbers NS036942, NS11739, R35GM136686, and partially through Aligning Science Across Parkinson’s ASAP-000580 and ASAP-020608 via the Michael J. Fox Foundation for Parkinson’s Research.
