A recent study published in Science Advances sheds light on the potential of enhancing glycolysis, specifically by targeting phosphoglycerate kinase 1 (PGK1), as a therapeutic strategy for Parkinson's disease (PD). The research, led by Tim Ryan at Weill Cornell Medicine, demonstrates that increasing PGK1 expression can restore function in neurons affected by PD-linked mutations, highlighting the enzyme's critical role in cellular energy production.
The Role of PGK1 in Neuronal Energy Production
Parkinson's disease, a progressive neurodegenerative disorder, is often associated with a decline in the brain's ability to fuel neurons adequately. As people age, this fueling process tends to worsen, contributing to the disease's progression. Ryan's work focuses on how neurons use energy, particularly at synapses, where cells communicate. The study reveals that PGK1, one of the ten enzymes involved in glycolysis, plays an outsized role in this process.
Terazosin's Unexpected Connection to PGK1
The investigation into PGK1's role was partly inspired by the work of Lei Liu at Capital Medical University, who discovered that terazosin, a drug typically used for prostate enlargement, had a surprising effect on cell survival. Liu's research indicated that terazosin interacted with PGK1, enhancing its function. Subsequent studies by Liu, Michael Welsh (University of Iowa), and Kumar Narayanan (University of Iowa) showed that terazosin slowed the progression of PD-like symptoms in animal models and correlated with fewer PD cases in patients using the drug for prostate enlargement.
PGK1 as the Rate-Limiting Step in Glycolysis
Ryan's team initially approached these findings with skepticism, questioning whether enhancing a single enzyme in the glycolytic pathway could significantly impact ATP synthesis. Their experiments, using cultured neurons with varying glucose availability, revealed that PGK1 is indeed the rate-limiting step in glycolysis. By monitoring ATP levels and synaptic vesicle recycling, the researchers found that increasing PGK1 expression allowed sugar-starved neurons to function similarly to those with adequate fuel.
Implications for Parkinson's Disease Treatment
To assess the therapeutic potential of enhancing PGK1 activity, the researchers examined neurons with mutations in synaptojanin 1 and DJ-1, two genes linked to PD. Overexpression of PGK1 or treatment with terazosin rescued the function of neurons with faulty synaptojanin 1, suggesting a potential therapeutic avenue for patients with this mutation. However, enhancing PGK1 activity did not rescue neurons with impaired DJ-1 genes, indicating a more complex relationship between the two proteins.
Further experiments involving mice injected with a neurotoxin showed that prophylactic overexpression of PGK1 protected against PD-like symptoms and neurodegeneration, reinforcing the idea that enhancing PGK1 activity can protect against PD.
Future Directions
While these findings are promising, neither Narayanan nor Ryan advocate for the immediate use of terazosin as a PD treatment. Instead, they emphasize that the study strengthens the theory that PD, regardless of its causes, is fundamentally a disorder of neuronal energetics. This work lays the groundwork for developing targeted treatments specifically designed to address these energetic deficits and combat the increasing prevalence of Parkinson's disease worldwide. According to Kumar Narayanan, “This study is a step towards the larger goals.”
