Researchers have uncovered a crucial role of a cell surface protein called Aplp1 in spreading the material responsible for Parkinson’s disease between brain cells. Promisingly, an FDA-approved cancer drug that targets another protein, Lag3, which interacts with Aplp1, has been shown to block this spread in mice, suggesting a potential therapy may already exist.

In a new study, an international team of scientists describes how Aplp1 and Lag3 work together to facilitate the entry of harmful alpha-synuclein protein clumps into brain cells.

“Now that we know how Aplp1 and Lag3 interact, we have a new way of understanding how alpha-synuclein contributes to the disease progression of Parkinson’s disease,” says Xiaobo Mao, a neuroscientist from Johns Hopkins University. “Our findings also suggest that targeting this interaction with drugs could significantly slow the progression of Parkinson’s disease and other neurodegenerative diseases.”

Parkinson’s disease, which affects over 8.5 million people worldwide, is the second most common neurodegenerative disease after Alzheimer’s. This progressive movement disorder is usually only diagnosed when symptoms appear, which include tremors, stiffness, balance problems, speech difficulties, disturbed sleep patterns, and mental health issues. Currently incurable, the disease often leads to significant physical impairments.

The primary symptoms of Parkinson’s result from the death or impairment of dopamine-producing neurons in the brain’s substantia nigra, a region involved in fine motor control. This is believed to be caused by Lewy bodies—abnormal protein clumps mostly composed of misfolded alpha-synuclein that travel between neurons. While alpha-synuclein typically helps maintain functional communication between neurons, problems arise when it becomes misfolded and insoluble, contributing to disease progression.

Previous studies on mice found that Lag3 binds to alpha-synuclein proteins and spreads Parkinson’s disease pathology in neurons. Although deleting Lag3 significantly hinders this process, it does not completely prevent it, indicating the involvement of another protein in the uptake of misfolded alpha-synuclein by neurons.

“Our work previously demonstrated that Lag3 wasn’t the only cell surface protein that helped neurons absorb alpha-synuclein, so we turned to Aplp1 in our most recent experiments,” says Johns Hopkins neuroscientist Valina Dawson.

The scientists conducted tests with genetically modified mice lacking either Aplp1, Lag3, or both. They discovered that Aplp1 and Lag3 can each independently help brain cells absorb harmful alpha-synuclein, but together they significantly increase the uptake. When both Aplp1 and Lag3 were absent, 90 percent less of the harmful alpha-synuclein entered healthy brain cells, indicating a greater blockade of the harmful protein clumps with the deletion of both proteins compared to just one.

The researchers administered the drug nivolumab/relatlimab, a melanoma medication containing a Lag3 antibody, to normal mice. They found that it also prevented Aplp1 and Lag3 from interacting, almost completely blocking the formation of disease-causing alpha-synuclein clumps in neurons.

“The anti-Lag3 antibody was successful in preventing the further spread of alpha-synuclein seeds in the mouse models and exhibited better efficacy than Lag3-depletion due to Aplp1’s close association with Lag3,” says Ted Dawson, a neuroscientist at Johns Hopkins University.

The next step will be to test the Lag3 antibody on mouse models of Parkinson’s disease and Alzheimer’s, where research has also identified Lag3 as a potential target.

By Impact Lab