In a study involving genetically engineered mice, researchers from Johns Hopkins Medicine have identified a potential new target involving Aplp1, a cell surface protein implicated in the propagation of alpha-synuclein, the protein associated with Parkinson’s disease. The findings in Nature Communications on May 31 illustrate how Aplp1 interacts with Lag3, another cell surface receptor, facilitating the spread of harmful alpha-synuclein proteins between brain cells, a hallmark of Parkinson’s disease.
The research underscores Lag3’s role as a target for a combination cancer drug already approved by the FDA, which utilises antibodies to direct the immune system towards eliminating specific targets. According to Xiaobo Mao, Ph.D., associate professor of neurology at Johns Hopkins University School of Medicine and a member of the Institute for Cell Engineering, understanding the Aplp1-Lag3 interaction provides new insights into alpha-synuclein’s role in Parkinson’s disease progression. Mao suggests that targeting this interaction with pharmaceutical interventions could potentially bring hope and optimism by slowing disease advancement in Parkinson’s and other neurodegenerative disorders.
The study, co-led by Mao and Ted Dawson, M.D., PhD, also involved Valina Dawson, PhD, and Hanseok Ko, PhD, all esteemed professors at Johns Hopkins University School of Medicine and researchers at the Institute for Cell Engineering. Previous research has established that misfolded alpha-synuclein proteins aggregate and move from one brain cell to another, causing cell death in dopamine-producing neurons—a process identified by Johns Hopkins researchers as parthanatos, a form of programmed cell death. This process leads to movement impairments, emotional instability, and cognitive decline, characteristic of Parkinson’s disease.
The researchers explain that Aplp1’s interaction with Lag3 on the cell surface facilitates the uptake of alpha-synuclein aggregates by healthy brain cells, ultimately contributing to their demise. Previous studies by Mao and Dawson’s team have highlighted Lag3’s role in binding with alpha-synuclein and promoting disease spread, with recent experiments focusing on Aplp1’s involvement in this process.
Using genetically modified mice lacking Aplp1, Lag3, or both proteins, researchers observed a significant reduction—up to 90%—in the uptake of harmful alpha-synuclein proteins by brain cells. Furthermore, administering the Lag3 antibody blocked the interaction between Aplp1 and Lag3, preventing healthy brain cells from absorbing disease-associated alpha-synuclein aggregates.
Ted Dawson notes that the Lag3 antibody, specifically nivolumab/relatlimab, approved for cancer treatment in 2022, demonstrated efficacy in halting the spread of alpha-synuclein seeds in mouse models. Due to Aplp1’s close association with Lag3, the antibody surpasses the effectiveness of Lag3 depletion alone.
The implications of this research extend beyond Parkinson’s disease, potentially influencing treatment approaches for other neurodegenerative conditions lacking definitive cures. In Alzheimer’s disease, characterised by memory loss, mood disturbances, and muscle problems, tau proteins undergo misfolding and aggregation in neurons, exacerbating the disease. Mao suggests that targeting Lag3, which also interacts with tau proteins implicated in dementia, with the same antibody approach could yield intriguing therapeutic benefits in Alzheimer’s research.
Following the promising outcomes with the Lag3 antibody in mice models, Ted Dawson outlines plans for future trials involving anti-Lag3 antibodies in both Parkinson’s and Alzheimer’s disease models. Additionally, Johns Hopkins researchers are exploring strategies to prevent unhealthy cells from releasing alpha-synuclein, potentially intercepting disease progression at an early stage. These promising outcomes should encourage and inspire the scientific community in future research and trials.
More information: Xiaobo Mao et al, Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein, Nature Communications. DOI: 10.1038/s41467-024-49016-3
Journal information: Nature Communications Provided by Johns Hopkins Medicine
