The skeptics were wrong. Using an engineered luminescent protein that lights up in the presence of ATP, Dr. Ryan’s team was able to visualize how levels of this essential metabolite change at the synapses — the junctions across which interconnected neurons communicate. In a highly-cited 2014 paper, they demonstrated that the excitation that precedes signaling leads to a surge in ATP production at the synaptic terminals of neurons.
“They’re constantly relying on a source of fuel to make the ATP from,” says Dr. Ryan. “We also showed then and in subsequent papers that if you didn’t let a synapse do this, it led to rapid collapse of synaptic function.” In particular, ATP production proved critical for the proper function of synaptic vesicles. These tiny membrane bubbles store neurotransmitter chemicals such as acetylcholine and dopamine; when a neuron is excited, the vesicles release these neurotransmitters into the synapse, triggering activation in the adjacent neuron.
Restoring the power in Parkinson’s
Parkinson’s disease is a neurodegenerative disease associated with the gradual loss of a specific subset of neurons that use dopamine to communicate, and which play a prominent role in both motor and cognitive function. The causes of Parkinson’s are poorly understood, but a growing body of evidence has indicated that degraded cellular metabolism plays a part. “As people age, we know that cellular energetics degrade,” says Dr. Nandakumar Narayanan, a clinical neurologist specializing in neurodegenerative disease at the University of Iowa. “We also know that in Parkinson’s disease, there’s a couple of genetic mutations and a couple of toxins that poison cells’ ability to handle and maintain energy.”
Dr. Ryan’s interest in Parkinson’s was initially piqued by a 2019 study from the lab of Dr. Michael Welsh, a pulmonologist at the University of Iowa. Dr. Welsh and colleagues including Dr. Narayanan had uncovered evidence that terazosin, an approved drug for benign prostatic hyperplasia (BPH), could also slow neuronal degeneration in various animal models of Parkinson’s, and that it did so by improving metabolic activity in neurons. They also determined that terazosin is most likely exerting this effect by binding to phosphoglycerate kinase 1 (PGK1), one link in a chain of enzymes that cells use to convert glucose into ATP.
Even more strikingly, Dr. Welsh and colleagues analyzed multiple patient databases and found that patients taking terazosin or chemically related drugs for BPH seemed to be protected against a subsequent Parkinson’s diagnosis. “For people starting at age 70 and going on for the next 10 years, the risk of getting Parkinson’s was reduced by 37%,” says Dr. Ryan. These intriguing findings spurred him to apply his team’s toolbox for measuring neuronal metabolism to this devastating and currently incurable disease.
“I felt the most important question we could ask was, ‘Is the target of terazosin really PGK1?’, because I didn’t believe it,” says Dr. Ryan. Indeed, the drug was initially developed to act on an entirely distinct protein with no role in metabolism whatsoever. But their results were unambiguous — PGK1 was the key to terazosin’s beneficial effects. In a 2024 paper, Dr. Ryan and colleagues demonstrated that treatment with this drug helps preserve ATP production and stabilize normal synaptic activity when cultured neurons are subjected to low glucose conditions that would otherwise impair their function.
In the absence of PGK1, terazosin lost its ability to preserve neuronal function, and the researchers also showed that they could mitigate the motor symptoms of Parkinson’s in a mouse model of the disease by artificially boosting PGK1 levels in brain cells. When Dr. Ryan and colleagues started dissecting how PGK1 exerts its protective effects, they uncovered evidence that this protein interacts with multiple other proteins with a known link to Parkinson’s disease. These results suggest that established risk factors for the disease may also work by disrupting healthy neuronal metabolism.
Dr. Narayanan was excited to see how this work helped flesh out the story that he and Dr. Welsh had outlined in their initial terazosin research. “That paper is really fundamental, innovative and, I think, criminally underrecognized,” he says, praising the Ryan lab’s methodical approach to dissecting complex biological processes in live brain cells. Dr. Narayanan has already conducted preliminary clinical trials to evaluate terazosin as a potential therapy for Parkinson’s, and believes Dr. Ryan’s work has given their efforts to conduct future efficacy studies additional momentum. “It establishes a cellular and molecular basis…for the clinical observations we’ve talked about,” he says.
Terazosin has the advantage of already being on the market, but Dr. Ryan also cautions that the drug also has antihypertensive effects that could put older patients at risk of dizziness and falls, and his team is now looking into alternative strategies for treating Parkinson’s based on their findings into neuronal metabolism.
A broader phenomenon
In parallel, Dr. Ryan is exploring how disrupted cellular metabolism contributes to neurological conditions besides Parkinson’s. For example, in a preprint posted to bioRxiv this past June, his team demonstrated that a gene mutation responsible for a rare disorder called early-onset epileptic encephalopathy (EOEE) also interferes with ATP production. They found that neuronal excitation activates the protein encoded by this gene, known as SLC13A5, which rapidly clears out metabolites that otherwise inhibit glucose metabolism. This allows activated neurons to rapidly generate the energy needed for synaptic signaling. When SLC13A5 is disabled, as in EOEE patients, normal synaptic function is impaired. However, Dr. Ryan’s team showed that this effect could be overcome by amplifying glucose metabolism by other means — including treatment with terazosin.
Similar defects in energy production are implicated in other forms of epilepsy as well, and Dr. Ryan has recently begun to explore these connections — and the therapeutic opportunities that they could unlock — with Dr. Juan Pascual, chief of the division of child neurology at Weill Cornell Medicine and NewYork-Presbyterian Komansky Children’s Hospital of Children’s Hospital of New York and a researcher focused on understanding the genetic foundations underlying such disorders. “We’ve taken a slightly different approach because we work on genetic models of metabolic failure linked to epilepsy — so they’re very complementary,” says Dr. Pascual, who was recruited to Weill Cornell Medicine as a professor of pediatrics, of neurology and of neuroscience and as the Abe M. Chutorian, MD Professor of Pediatric Neurology. “Thanks to Tim and other people, it’s very clear that you need to know both ways of talking if you really want to make an impact, so I think that’s been radically transformative.”
