Cancer drug may target protein linked to Parkinson's disease, study finds

In recent research, scientists at Johns Hopkins Medicine have unveiled a new biological target linked to the progression of Parkinson's disease. This target involves Aplp1, a protein found on cell surfaces, which facilitates the spread of the disease-causing protein alpha-synuclein. This discovery, detailed in a study published on May 31 in Nature Communications, sheds light on the interaction between Aplp1 and another cell surface receptor, Lag3. This interaction is crucial in the process through which harmful alpha-synuclein proteins spread to brain cells, contributing to the development of Parkinson's disease.

Alpha-synuclein protein buildups are a characteristic feature of Parkinson's disease. The research team, led by Xiaobo Mao and Ted Dawson, has identified how Aplp1 and Lag3 work together in this process. Intriguingly, Lag3 is already targeted by a cancer treatment drug approved by the U.S. Food and Drug Administration (FDA). This drug employs antibodies that help the human immune system identify and eliminate harmful cells.

Dr. Mao, an associate professor of neurology at Johns Hopkins University School of Medicine, explained that understanding the interaction between Aplp1 and Lag3 offers new insights into the role of alpha-synuclein in Parkinson's disease progression. The findings suggest that targeting this interaction with drugs could potentially slow the disease's advancement and other neurodegenerative conditions.

The team’s research builds on previous studies that revealed the role of misfolded alpha-synuclein proteins in spreading Parkinson's disease by traveling from one brain cell to another. These misfolded proteins kill dopamine-producing brain cells, which leads to symptoms such as movement impairments, emotional instability, and cognitive decline. The researchers have identified that the process, known as parthanatos, involves cell death caused by these protein buildups.

The recent study using genetically engineered mice demonstrated that Aplp1’s connection with Lag3 enables healthy brain cells to absorb clumps of alpha-synuclein, leading to cell death. In earlier studies from 2016 and 2021, Mao and Dawson's team found that Lag3 binds with alpha-synuclein, facilitating the disease's spread. However, these studies also indicated that another protein was partly responsible for the absorption of misfolded alpha-synuclein.

To confirm Aplp1’s role, the researchers used genetically engineered mice lacking Aplp1, Lag3, or both. They observed a 90% reduction in the absorption of harmful alpha-synuclein in mice without both proteins. Additionally, when they treated the mice with the Lag3 antibody, it blocked the interaction between Aplp1 and Lag3, preventing healthy brain cells from absorbing the disease-causing protein clumps.

The FDA-approved Lag3 antibody nivolumab/relatlimab, used in cancer treatment, could potentially prevent the absorption of alpha-synuclein by cells. According to Ted Dawson, the antibody was more effective than just depleting Lag3 due to Aplp1's close association with Lag3.

This research may also have implications for treating other neurodegenerative diseases, such as Alzheimer's disease, where tau proteins misfold and accumulate in neurons, exacerbating the condition. Scientists could explore targeting Lag3, which also binds with tau proteins, using the same antibody.

Based on the promising results in mice, the next steps include conducting trials with the anti-Lag3 antibody in mice with Parkinson's and Alzheimer's diseases. The Johns Hopkins research team is also investigating ways to prevent the release of disease-causing alpha-synuclein from unhealthy cells initially.