Pathological α-synuclein (α-syn) can spread between cells in part by binding to lymphocyte activation gene 3 (Lag3). Recently, in a research report published in the international journal Nature Communications, scientists from Johns Hopkins University School of Medicine and other institutions have identified a potential new biological target involving Aplp1, a cell surface protein that can drive the spread of α-synuclein that causes Parkinson's disease.
Related research revealed how Aplp1 connects with another cell surface receptor, Lag3, which plays an important role in helping harmful alpha-synuclein spread to brain cells. The accumulation of these proteins is a hallmark of Parkinson's disease. Notably, Lag3 has become the target of an FDA-approved combination cancer drug that uses antibiotics to "teach" human immune cells to perform seek-and-destroy functions. "Now that we know how Aplp1 interacts with Lag3, we have a new way to understand how alpha-synuclein promotes the progression of Parkinson's disease," said Xiaobo Mao, Ph.D., a researcher at the Institute for Oncology and the Department of Oncology.
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The results of this paper also suggest that targeting and drug interactions may significantly slow the progression of Parkinson's disease and other neurodegenerative diseases. Long-standing research results show that by accumulating together and forming protein deposits, misfolded alpha-synuclein can travel from brain cell to brain cell, killing nerve cells responsible for producing dopamine and causing Parkinson's disease to progress through a type of programmed cell death. This process of dependent cell death (parthanatos) leads to disorders of body movement, emotional regulation and thinking.
Figure 1. α-Syn PFF binds to Aplp1. (Mao X, et al., 2024)
The researchers say that the binding of Aplp1 to cell-surface Lag3 promotes the uptake of mobile alpha-synuclein by healthy brain cells, leading to cell death. In mouse studies published between 2016 and 2021, Mao et al. identified Lag3's important role in binding to alpha-synuclein, which leads to the spread of Parkinson's disease. However, these findings suggest that another protein is partly responsible for the cell's uptake of misfolded alpha-synuclein. Previously, researchers found that Lag3 is not the only cell-surface protein that helps neurons take up alpha-synuclein, so in the recent study, they turned to Aplp1.
To determine whether Aplp1 does promote the spread of harmful alpha-synuclein, the researchers used a group of genetically engineered mice that lacked Aplp1 or Lag3, or both Aplp1 and Lag3. In mice lacking Aplp1 and Lag3, the uptake of harmful alpha-synuclein by their cells was reduced by 90%. When mice were injected with Lag3 antibodies, the researchers found that the drug also blocked the interaction between Aplp1 and Lag3, meaning that healthy brain cells no longer took up pathogenic α-synuclein clumps. The researchers said that the Lag3 antibody nivolumab (a cancer drug approved by the FDA in 2022) plays an important role in preventing cells from taking up α-synuclein.
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"The anti-Lag3 antibody successfully blocked further spread of alpha-synuclein seeds in the mouse model and showed better efficacy than Lag3 depletion due to the close association between Aplp1 and Lag3," said Dawson. This study has potential applications in treating other neurodegenerative diseases that are currently incurable. Alzheimer's disease is often associated with symptoms such as memory loss, mood swings and muscle problems, in which tau protein often misfolds and exists at high levels in neurons, further exacerbating disease symptoms. In Alzheimer's research, researchers can use the same antibody to repeatedly try to target Lag3, which binds to tau protein associated with dementia.
Finally, the researchers said that with the success of using Lag3 antibodies in mice, they will next test anti-Lag3 antibodies in mice with Parkinson's disease and Alzheimer's disease. At the same time, the researchers are also studying how to prevent unhealthy cells from releasing pathogenic alpha-synuclein in the first place.
Reference
Mao X, et al. Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein. Nature Communications, 2024, 15(1): 4663.