Aging Midbrain Neurons Face Energy Crisis Linked to Parkinson’s
December 5, 2025
An immunofluorescent image of a dopamine neuron expressing glycogen in the cell body and axons. Credit: Dr. Camila Pulido.
A study led by Weill Cornell Medicine investigators reveals a potential explanation for the degeneration of dopamine neurons in Parkinson’s disease. These neurons, located in the midbrain, may face a vicious cycle of decline due to energy shortages. The research, published in the Proceedings of the National Academy of Sciences, sheds light on the high energy demands of midbrain dopamine neurons and their unique glycogen storage mechanisms.
The scientists discovered that under normal conditions, these neurons create a fuel reserve in the form of glycogen, allowing them to function for an extended period even when their glucose supply is interrupted. However, the neurons' glycogen regulation leaves them vulnerable to glucose shortages, especially as their functions decline with aging. This vulnerability may explain the deaths of these midbrain neurons in Parkinson’s, aligning with the idea that energy insufficiency is a common failure mode in neurological disorders.
Midbrain dopamine neurons, particularly in the substantia nigra pars compacta, play a crucial role in regulating voluntary muscle movements and learning and motivation. Their degeneration in Parkinson’s is associated with muscle rigidity and other motor symptoms. The study's senior author, Dr. Timothy Ryan, suggests that a combination of aging, environmental factors, and genetic risk factors can lead to reduced dopamine output, causing these neurons to become less resilient to glucose shortages and ultimately degenerate.
The research team, including Dr. Camila Pulido, observed that rat midbrain dopamine neurons are resilient to glucose supply interruptions. They confirmed the neurons' ability to create glycogen fuel reserves, similar to some muscle cells, using a special glycogen-detecting antibody. The team then uncovered a unique regulation mechanism where dopamine output influences glycogen synthesis through D2 receptors on output terminals. This regulation creates a potential danger, as reduced dopamine output leads to less glycogen storage, making the neurons highly sensitive to glucose deprivation.
The study's findings suggest that interventions to enhance midbrain dopamine neurons' resilience to glucose shortages could prevent Parkinson’s or slow its progression. The researchers plan to explore glycogen storage in other neuron types, aiming to understand the variations in glycogen storage across different dopamine neuron populations in the nervous system.
