A groundbreaking discovery in Parkinson’s disease research suggests that an existing FDA-approved cancer drug could potentially offer new hope for treating the neurodegenerative disorder.
Researchers have identified a critical role for a cell surface protein, Aplp1, in the spread of Parkinson’s disease-related protein clumps within the brain. Significantly, an FDA-approved cancer medication targeting another protein, Lag3, appears to block this spread in mice, raising the possibility that an effective therapy may already be on the market.
In a study published last year, an international team of scientists described how Aplp1 and Lag3 interact to facilitate the entry of harmful alpha-synuclein clumps into brain cells—key contributors to Parkinson’s disease progression.
“We now have a new understanding of how Aplp1 and Lag3 interact, shedding light on how alpha-synuclein drives Parkinson’s disease,” said Xiaobo Mao, a neuroscientist at Johns Hopkins University. “Our findings suggest that targeting this interaction with drugs could slow the progression of Parkinson’s and other neurodegenerative diseases.”
Parkinson’s disease, affecting more than 8.5 million people globally, is the second most common neurodegenerative disorder after Alzheimer’s. It is primarily a movement disorder that progresses over time, with symptoms including tremors, stiffness, balance issues, speech difficulties, disrupted sleep, and mental health problems. As of now, there is no cure, and patients may ultimately lose the ability to walk or speak.
The disease primarily results from the degeneration of dopamine-producing neurons in the substantia nigra, a brain region essential for motor control. This degeneration is thought to be caused by Lewy bodies, abnormal protein clumps mostly made of misfolded alpha-synuclein, which spread from one neuron to another.
Under normal circumstances, alpha-synuclein helps neurons communicate. However, when the protein misfolds and becomes insoluble, it can cause cellular damage. Researchers have long struggled to determine whether this misfolding is a direct cause of Parkinson’s disease or merely a symptom of its progression.
Previous studies on mice found that Lag3 binds to alpha-synuclein, helping it spread in brain cells. While eliminating Lag3 significantly slowed this process, it did not fully prevent it. This led researchers to explore the role of other proteins, such as Aplp1, in the absorption of misfolded alpha-synuclein.
“We previously showed that Lag3 wasn’t the only protein involved in alpha-synuclein uptake,” said Valina Dawson, a neuroscientist at Johns Hopkins. “In our recent experiments, we focused on Aplp1.”
In their experiments with genetically modified mice, the researchers discovered that both Aplp1 and Lag3 individually facilitated the absorption of alpha-synuclein into brain cells. However, when both proteins were absent, the uptake of harmful alpha-synuclein dropped by 90 percent.
The team then tested nivolumab/relatlimab, a melanoma drug containing an antibody against Lag3, on normal mice. The treatment effectively blocked the interaction between Aplp1 and Lag3, nearly halting the formation of alpha-synuclein clumps in neurons.
“The anti-Lag3 antibody prevented the spread of alpha-synuclein in the mouse models, demonstrating even better efficacy than simply removing Lag3,” said Ted Dawson, a neuroscientist at Johns Hopkins.
Next steps include testing the Lag3-targeting antibody in mouse models of Parkinson’s disease and Alzheimer’s, as research suggests Lag3 could also play a role in the latter.
The research, published in Nature Communications, offers a promising new direction for Parkinson’s treatment, with the potential to repurpose existing FDA-approved drugs for a neurodegenerative disease that has long lacked effective therapies.
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