Cancer Drug Shows Promise in Blocking Parkinson's Disease Spread in Mouse Models
核心洞察
Researchers identified Aplp1 (搜索) as a key protein in spreading alpha-synuclein (搜索), the protein clumps responsible for Parkinson's disease (搜索), between brain cells.
An FDA-approved cancer (搜索) drug targeting Lag3 (搜索), which interacts with Aplp1 (搜索), effectively blocked the spread of alpha-synuclein (搜索) in mice, suggesting a potential therapeutic strategy.
The study demonstrated that Aplp1 (搜索) and Lag3 (搜索) independently facilitate the uptake of harmful alpha-synuclein (搜索), with their combined action significantly increasing this uptake.
A recent study has uncovered a novel mechanism by which Parkinson's disease (搜索) spreads in the brain, identifying the Aplp1 (搜索) protein as a key player in the cell-to-cell transfer of harmful alpha-synuclein (搜索) clumps. Importantly, the research suggests that an existing FDA-approved cancer (搜索) drug, which targets the Lag3 (搜索) 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 (搜索) and Lag3 (搜索) work together to facilitate the entry of misfolded alpha-synuclein (搜索) 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 (搜索)."
Aplp1 and Lag3: A Collaborative Pathway
Previous research had implicated Lag3 (搜索) in binding to alpha-synuclein (搜索) 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 (搜索) in our most recent experiments."
Experiments with genetically modified mice lacking Aplp1 (搜索), Lag3 (搜索), or both revealed that both proteins can independently assist brain cells in absorbing harmful alpha-synuclein (搜索). 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 (搜索) antibody, on normal mice. They found that the drug effectively prevented Aplp1 (搜索) and Lag3 from interacting, almost completely blocking the formation of disease-causing alpha-synuclein (搜索) 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 (搜索), 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 (搜索) antibody in mouse models of both Parkinson's and Alzheimer's (搜索) 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.