A new study suggests that dopamine-producing neurons in the midbrain become increasingly vulnerable with age because of an internal energy imbalance that can spiral into degeneration, offering a potential explanation for their loss in Parkinson’s disease. Led by researchers at Weill Cornell Medicine, the work indicates that these neurons face a unique risk of fuel shortages that worsen as their function declines, creating a self-reinforcing cycle of damage.
The findings, published on 5 December in the Proceedings of the National Academy of Sciences, focus on how midbrain dopamine neurons meet their unusually high energy demands. These cells have exceptionally extensive branching, allowing them to influence many target neurons but also requiring substantial energy to sustain signalling. The researchers found that, under normal conditions, dopamine neurons protect themselves by storing glucose as glycogen. This internal reserve enables them to continue functioning for an unexpectedly long time, even when the continuous supply of glucose from the blood is interrupted.
However, the study also reveals a critical weakness in how these neurons manage their fuel. Glycogen storage is not static but tightly regulated by the neurons’ own dopamine signalling. When dopamine output is strong, glycogen synthesis is maintained, preserving energy resilience. As neurons age and dopamine release begins to decline—a process observed even in normal ageing—glycogen stores are reduced. This leaves the cells increasingly exposed to glucose shortages at precisely the stage when they are least able to cope.
“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 senior author Timothy Ryan. His comment situates the findings within a broader shift in neuroscience, which views metabolic stress as a central driver of neurodegeneration rather than a secondary effect.
The affected neurons are located in the substantia nigra pars compacta, which plays a key role in voluntary movement, learning, and motivation. Their degeneration is responsible for the hallmark motor symptoms of Parkinson’s disease, such as rigidity and slowed movement. While it has long been known that these neurons decline in Parkinson’s and gradually decrease with age, the reasons for their selective vulnerability have remained unclear. This study provides evidence that energy handling, rather than toxic by-products alone, may be a crucial factor.
In experiments on rat neurons, the team—including first author Camila Pulido—showed for the first time that neurons can directly synthesise glycogen, challenging the long-held view that this fuel reserve is confined mainly to muscle and liver tissue. They also demonstrated that when glycogen stores were exhausted, dopamine neurons became extremely sensitive to glucose deprivation, losing function almost immediately. The researchers propose that ageing, genetic risk factors, and environmental stressors may together push these neurons into a vicious cycle of declining dopamine output, shrinking energy reserves, and eventual cell death.
If this model is correct, it suggests new therapeutic possibilities. Interventions that enhance the ability of midbrain dopamine neurons to store or access energy could potentially slow the onset or progression of Parkinson’s disease. The team now plans to examine glycogen storage in other neuron populations, aiming to understand why some neurons are more resilient to metabolic stress than others and how this resilience might be strengthened.
More information: Camila Pulido et al, Neuromodulatory control of energy reserves in dopaminergic neurons, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2523019122
Journal information: Proceedings of the National Academy of Sciences Provided by Weill Cornell Medicine
