Cancer drug could help prevent Parkinson’s disease, study finds
Our findings suggest that targeting this interaction with drugs could significantly slow the progression of Parkinson’s disease
Lag3 is already targeted by a combination cancer drug approved by the U.S. Food and Drug Administration (FDA). This drug uses antibodies to “teach” the human immune system to recognize and destroy specific targets. (CREDIT: Creative Commons)
In recent studies involving genetically engineered mice, researchers at Johns Hopkins Medicine have identified a potentially new biological target involving Aplp1, a cell surface protein that facilitates the spread of Parkinson’s disease-causing alpha-synuclein.
Published in Nature Communications, the research reveals how Aplp1 interacts with Lag3, another cell surface receptor. This interaction plays a critical role in spreading harmful alpha-synuclein proteins to brain cells. These protein buildups are hallmarks of Parkinson’s disease.
Interestingly, Lag3 is already targeted by a combination cancer drug approved by the U.S. Food and Drug Administration (FDA). This drug uses antibodies to “teach” the human immune system to recognize and destroy specific targets.
“Now that we understand how Aplp1 and Lag3 interact, we have a new perspective on how alpha-synuclein contributes to Parkinson’s disease progression,” says Dr. Xiaobo Mao, associate professor of neurology at 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 and other neurodegenerative diseases.”
The research was co-led by Dr. Mao and Dr. Ted Dawson, Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and director of the Johns Hopkins Institute for Cell Engineering. Other contributors included Dr. Valina Dawson and Dr. Hanseok Ko, both professors of neurology and members of the Institute for Cell Engineering.
Previous studies have shown that misfolded alpha-synuclein proteins form clumps that travel from brain cell to brain cell, killing those responsible for producing dopamine, and causing Parkinson’s to progress through a type of programmed cell death known as parthanatos. This process leads to impairments in movement, emotional regulation, and cognition.
The bond between Aplp1 and Lag3 on the cell surface enables healthy brain cells to absorb these clumps of alpha-synuclein, resulting in cell death.
In their 2016 and 2021 mouse studies, Mao and Dawson’s team identified Lag3’s role in binding with alpha-synuclein proteins, causing Parkinson’s to spread. However, these studies suggested another protein was also involved in the cell’s absorption of misfolded alpha-synuclein.
“Our previous work showed that Lag3 wasn’t the only cell surface protein aiding in the absorption of alpha-synuclein by neurons, so we investigated Aplp1 in our recent experiments,” explains Dr. Valina Dawson.
To test whether Aplp1 contributed to the spread of harmful alpha-synuclein proteins, researchers used genetically engineered mice lacking either Aplp1, Lag3, or both. In mice missing both Aplp1 and Lag3, cell absorption of harmful alpha-synuclein dropped by 90%. After injecting these mice with the Lag3 antibody, they found that this drug blocked the interaction between Aplp1 and Lag3, preventing healthy brain cells from absorbing disease-causing alpha-synuclein clumps.
The researchers suggest that the Lag3 antibody nivolumab/relatlimab, an FDA-approved cancer treatment drug since 2022, could help prevent cells from absorbing alpha-synuclein.
“The anti-Lag3 antibody successfully prevented further spread of alpha-synuclein seeds in the mouse models and showed better efficacy than Lag3 depletion due to Aplp1’s close association with Lag3,” says Dr. Ted Dawson.
This research holds potential applications for treating other neurodegenerative conditions that currently have no cures. In Alzheimer’s disease, for example, tau proteins become misfolded and clump together in neurons, worsening the condition. Researchers could target Lag3, which also binds with dementia-related tau protein, using the same antibody approach.
Given the success of using the Lag3 antibody in mice, the next steps involve conducting anti-Lag3 antibody trials in mice with Parkinson’s and Alzheimer’s diseases. The Johns Hopkins team is also exploring ways to prevent unhealthy cells from releasing disease-causing alpha-synuclein in the first place.
Other researchers on this study are Hao Gu, Donghoon Kim, Yasuyoshi Kimura, Ning Wang, Enquan Xu, Ramhari Kumbhar, Xiaotian Ming, Haibo Wang, Chan Chen, Shengnan Zhang, Chunyu Jia, Yuqing Liu, Hetao 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.
Note: Materials provided above by the The Brighter Side of News. Content may be edited for style and length.
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