The groundbreaking research conducted by Johns Hopkins Medicine has uncovered a potential new target for combating Parkinson’s disease, focusing on the role of Aplp1, a cell surface protein that fuels the spread of harmful alpha-synuclein proteins. Published in Nature Communications, the study highlights how Aplp1 interacts with Lag3, another cell surface receptor, to facilitate the transmission of alpha-synuclein to brain cells, a hallmark of Parkinson’s disease.
Dr. Xiaobo Mao, along with a team of researchers including Dr. Ted Dawson, discovered that targeting the interaction between Aplp1 and Lag3 could slow down the progression of Parkinson’s disease. By disrupting this process with drugs, they believe it is possible to significantly reduce the spread of alpha-synuclein and prevent cell death in the brain.
Alpha-synuclein proteins are known to form clumps and travel from one brain cell to another, disrupting the production of dopamine and leading to the progression of Parkinson’s disease through programmed cell death. Aplp1’s connection with Lag3 on the cell surface allows the absorption of these harmful proteins by healthy brain cells, ultimately causing their demise.
Previous research by Mao and Dawson identified Lag3’s role in binding with alpha-synuclein proteins, but further investigation revealed that Aplp1 also plays a crucial role in this process. Using genetically engineered mice lacking Aplp1 or Lag3, the researchers demonstrated a 90% reduction in the absorption of harmful alpha-synuclein proteins. Additionally, treatment with the Lag3 antibody effectively blocked the interaction between Aplp1 and Lag3, preventing the uptake of disease-causing protein clumps by healthy brain cells.
The potential of the Lag3 antibody, nivolumab/relatlimab, approved for cancer treatment in 2022, in preventing the spread of alpha-synuclein seeds in mice showcases a promising avenue for future therapeutic interventions in Parkinson’s and other neurodegenerative diseases. The researchers are also exploring the possibility of using the same antibody to target tau proteins in Alzheimer’s disease, another neurodegenerative condition characterized by protein buildup in the brain.
Moving forward, the team plans to conduct anti-Lag3 antibody trials in mouse models of Parkinson’s and Alzheimer’s disease to further explore the therapeutic potential of this approach. By understanding how to prevent the release of disease-causing alpha-synuclein from unhealthy cells, they hope to develop more effective treatments for these devastating conditions.
This groundbreaking research, supported by grants from various organizations including the National Institutes of Health, the Parkinson’s Foundation, and the American Parkinson Disease Association, offers hope for the future of neurodegenerative disease treatment. By targeting the interaction between Aplp1 and Lag3, researchers are paving the way for innovative therapies that could slow down the progression of Parkinson’s disease and improve the quality of life for millions of patients worldwide.
