A recent study has uncovered a novel mechanism by which Parkinson's disease spreads in the brain, identifying the Aplp1 protein as a key player in the cell-to-cell transfer of harmful alpha-synuclein clumps. Importantly, the research suggests that an existing FDA-approved cancer drug, which targets the Lag3 protein, can effectively block this spread in mice, opening new avenues for potential Parkinson's therapies.
The international team of scientists detailed in a Nature Communications paper how Aplp1 and Lag3 work together to facilitate the entry of misfolded alpha-synuclein into brain cells. Xiaobo Mao, a neuroscientist from Johns Hopkins University, noted, "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."
Aplp1 and Lag3: A Collaborative Pathway
Previous research had implicated Lag3 in binding to alpha-synuclein and promoting the spread of Parkinson's pathology. However, deleting Lag3 alone did not completely prevent the process, suggesting the involvement of other proteins. Valina Dawson, another neuroscientist at Johns Hopkins, explained, "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."
Experiments with genetically modified mice lacking Aplp1, Lag3, or both revealed that both proteins can independently assist brain cells in absorbing harmful alpha-synuclein. However, the combined absence of both Aplp1 and Lag3 resulted in a 90% reduction in the uptake of the harmful protein, highlighting their synergistic effect.
Cancer Drug Shows Promise
The researchers then tested the melanoma medication nivolumab/relatlimab, which contains a Lag3 antibody, on normal mice. They found that the drug effectively prevented Aplp1 and Lag3 from interacting, almost completely blocking the formation of disease-causing alpha-synuclein clumps in neurons. Ted Dawson, a neuroscientist at Johns Hopkins University, stated, "The anti-Lag3 antibody was successful in preventing further spread of alpha-synuclein seeds in the mouse models and exhibited better efficacy than Lag3-depletion because of Aplp1's close association with Lag3."
Implications and Future Directions
With over 8.5 million people worldwide affected by Parkinson's, the second most common neurodegenerative disease after Alzheimer's, the need for effective treatments is critical. The current study offers a promising lead, suggesting that repurposing existing drugs could provide a new therapeutic approach.
The next step involves testing the Lag3 antibody in mouse models of both Parkinson's and Alzheimer's disease, where Lag3 has also been identified as a potential therapeutic target. These future studies will further elucidate the potential of this approach in combating neurodegenerative diseases.
