Dopamine neurons in a part of the brain called the midbrain may, with aging, be increasingly susceptible to a vicious spiral of decline driven by fuel shortages, according to a study led by Weill Cornell Medicine investigators. The findings offer a potential explanation for the degeneration of this neuron population in Parkinson’s disease.
In the study, published Dec. 5 in the Proceedings of the National Academy of Sciences, the scientists examined how midbrain dopamine neurons, which have unusually numerous output branches, handle their high energy requirements. They showed that these neurons under normal conditions create a fuel reserve in the form of clusters of glucose molecules called glycogen. This allows the neurons to keep working for a surprisingly long time even when their usual supply of glucose from the blood is interrupted. However, the researchers also discovered that the neurons regulate their glycogen storage in a way that can leave them highly vulnerable to glucose shortages, especially as their functions begin to decline with aging.
Dr. Timothy Ryan. Credit: Travis Curry
“This vulnerability may explain the deaths of these midbrain neurons in Parkinson’s and is consistent with the idea that energy insufficiency is a common failure mode in neurological disorders,” said study senior author Dr. Timothy Ryan, the Tri-Institutional Professor of Biochemistry and Biophysics and a professor of biochemistry in anesthesiology at Weill Cornell Medicine.
Midbrain dopamine neurons—specifically in a region called the substantia nigra pars compacta—help regulate voluntary muscle movements as well as learning and motivation. Their degeneration in Parkinson’s accounts for the classic muscle rigidity and other “motor signs” of the disease. Why most of these neurons degenerate in Parkinson’s is still not clear, though there is evidence that their functions begin to decline and their numbers decrease even with ordinary aging.
In the new study, Dr. Ryan and his team, including first author Dr. Camila Pulido, a research associate in biochemistry and biophysics, observed that rat midbrain dopamine neurons are remarkably resilient to interruptions in the usually continuous supply of glucose. Suspecting that these neurons create their own glycogen fuel reserve, as some muscle cells do, they confirmed this using a special glycogen-detecting antibody—the first direct demonstration that neurons make glycogen.
Dr. Maria Pulido. Photo provided.
The team then discovered that these dopamine neurons regulate their synthesis of glycogen using dopamine-sensing receptors—known as D2 receptors—on their own output terminals. Thus, more dopamine output means more D2 receptor activity and more glycogen storage. But this unexpected form of regulation creates a potentially dangerous vulnerability, in which less dopamine output leads to less glycogen storage. As the team’s experiments showed, when the neurons had no more glycogen stores, they became hypersensitive to glucose deprivation, ceasing to function almost immediately.
The researchers hypothesize that some combination of aging, environmental exposures and genetic risk factors can cause declines in these neurons’ dopamine outputs that result in reduced fuel resilience, worsening dysfunction and ultimately degeneration. They note that many of the known gene mutations linked to Parkinson’s cause impairments of cellular fuel supply and thus would increase the tendency for these neurons to enter this destructive spiral.
“Also consistent with our hypothesis is the fact that some antipsychotic medications, which reduce the activity of D2 receptors, presumably reducing glycogen storage in these neurons, can cause Parkinson’s-like movement dysfunctions as side effects,” Dr. Ryan said.
If this hypothesis is correct, then interventions to improve midbrain dopamine neurons’ resilience to glucose shortages might be able to prevent Parkinson’s or arrest its progress once it starts.
The researchers now plan to follow up with studies of glycogen storage in other types of neurons.
“We want to look first at how different dopamine neuron populations across the nervous system differ in their storage of glycogen,” Dr. Pulido said.
The research described in this story was funded in part by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, through grant numbers R01NS11739 and R35NS116824, and in part by Aligning Science Across Parkinson’s grant numbers ASAP-000580 and ASAP-024404 through the Michael J. Fox Foundation for Parkinson’s Research.