Researchers at Johns Hopkins Medicine have discovered a new potential biological target involving Aplp1, a cell surface protein linked to the spread of Parkinson’s disease-causing alpha-synuclein. In studies with genetically engineered mice, the findings published on May 31 in Nature Communications show how Aplp1 connects with Lag3.Another protein found on the surface of cells, known as Lag3, plays a crucial role in the process of spreading harmful alpha-synuclein proteins to brain cells. These protein buildups are characteristic of Parkinson’s disease. The researchers highlight that Lag3 is already the focus of a cancer drug approved by the U.S. Food and Drug Administration (FDA) that uses antibodies to instruct the human immune system on what to target and eliminate. “Now that we understand how Aplp1 and Lag3 interact, we have a new perspective on how alpha-synuclein contributes to the progression of Parkinson’s disease,” explains Xiaobo Mao, Ph.D., who serves as an associate professor of neurology.The Johns Hopkins University School of Medicine and a member of the Institute for Cell Engineering. “Our findings also suggest that targeting this interaction with drugs could significantly slow the progression of Parkinson’s disease and other neurodegenerative diseases.”
Mao co-led the research along with Ted Dawson, M.D., Ph.D., Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Institute for Cell Engineering, Valina Dawson, Ph.D. and Hanseok Ko, Ph.D., professors of neurology at the school of medicine and members of the Institute fo
Cell Engineering.
Research has shown that misfolded alpha-synuclein proteins can form protein deposits and spread from brain cell to brain cell. This process kills cells responsible for producing dopamine and leads to the progression of Parkinson’s disease. Johns Hopkins researchers have identified a type of “programmed” cell death, called parthanatos, which is responsible for impairments in movement, emotional regulation, and thinking.
The bond between Aplp1 and Lag3 on the cell’s surface allows healthy brain cells to absorb clumps of alpha-synuclein as they travel.
According to the researchers, Aplp1, in conjunction with Lag3, plays a significant role in facilitating the absorption of misfolded alpha-synuclein by neurons, ultimately leading to cell death.
Mao and Dawson’s team conducted mouse studies in 2016 and 2021, which revealed that Lag3 binds with alpha-synuclein proteins, contributing to the spread of Parkinson’s disease. However, the studies also suggested that another protein was partially responsible for the cell’s absorption of misfolded alpha-synuclein.
Valina Dawson explains, “Our previous work showed that Lag3 wasn’t the sole contributor to the absorption of alpha-synuclein by neurons, so we decided to explore the role of Aplp1 in our most recent experiments.”
In order to confirm the involvement of Aplp1, further experiments were conducted.The researchers conducted a study on genetically engineered mice to investigate how the absence of Aplp1 and Lag3 affects the absorption of harmful alpha-synuclein proteins. They found that in mice lacking both Aplp1 and Lag3, there was a significant decrease of 90% in cell absorption of the harmful protein. Furthermore, when the mice were injected with the Lag3 antibody, it was discovered that the drug blocks the interaction of Aplp1 and Lag3, preventing healthy brain cells from absorbing the disease-causing alpha-synuclein clumps.
The researchers believe that the Lag3 antibody nivolumab/relatlimab, which is an FDA-approved drug for cancer treatment, may have potential in preventing cells from absorbing harmful alpha-synuclein proteins.The anti-Lag3 antibody has been successful in stopping the further spread of alpha-synuclein seeds in mouse models, and it has shown better efficacy than Lag3-depletion due to Aplp1’s close association with Lag3, according to Ted Dawson. This research has the potential to be used in treating other neurodegenerative conditions that currently have no cures, Mao says. In Alzheimer’s disease, which is linked to symptoms such as memory loss, mood instability, and muscle problems, tau proteins become misfolded and clump together in neurons at high levels, worsening the condition. In Alzheimer’s research, scientists could experiment with.Targeting Lag3, which also interacts with the dementia-related tau protein, using the same antibody. Ted Dawson mentioned that after successfully using the Lag3 antibody in mice, the next steps would involve conducting anti-Lag3 antibody trials in mice with Parkinson’s disease and Alzheimer’s disease. The researchers at Johns Hopkins are also investigating methods to prevent unhealthy cells from releasing disease-causing alpha-synuclein. Other researchers involved in this study include Hao Gu, Donghoon Kim, Yasuyoshi Kimura, Ning Wang, Enquan Xu, Ramhari Kumbhar, Xiaotian Ming, Haibo Wang, Chan Chen, Shengnan Zhang, Chunyu Jia, Yuqing Liu, and H.etao Bian, Senthilkumar Karuppagounder, Fatih Akkentli, Qi Chen, Longgang Jia, Heehong Hwang, Su Hyun Lee, Xiyu Ke, Michael Chang, Amanda Li, Jun Yang, Cyrus Rastegar, Manjari Sriparna, Preston Ge, Saurav Brahmachari, Sangjune Kim, Shu Zhang, Haiqing Liu, Sin Ho Kweon, Mingyao Ying and Han Seok Ko from Johns Hopkins; Yasushi Shimoda from the Nagaoka University of Technology; Martina Saar and Ulrike Muller from Heidelberg University; Creg Workman and Dario Vignali of the University of Pittsburgh School of Medicine and Cong Liu of the Chinese Academy of Sciences.
This work was supported by grants from the National Institutes of Health (NIH).01NS107318, R01AG073291, R01AG071820, 1135 RF1NS125592, K01AG056841, R21NS125559, R01NS107404, P01AI108545, R01AI144422), the Parkinson’s Foundation, the Maryland Stem Cell Research Foundation, the American Parkinson Disease Association, the Uehara Memorial Foundation, the JPB Foundation, the Adrienne Helis Malvin Medical Research Foundation, and the Parkinson’s Disease Foundation.
