Summary: Researchers have discovered a new therapeutic target for Parkinson’s disease, the Aplp1 protein, which facilitates the spread of harmful alpha-synuclein proteins in the brain. Notably, an FDA-approved cancer drug targeting Lag3, a protein that interacts with Aplp1, has shown promise in blocking this spread in mouse models.
This groundbreaking research suggests the possibility of repurposing existing cancer therapies for Parkinson’s disease and other neurodegenerative diseases.
Highlights:
- Aplp1 and Lag3 interaction is crucial for the spread of alpha-synuclein in the brain.
- An FDA-approved cancer drug, nivolumab/relatlimab, targeting Lag3, shows the potential to block this interaction.
- This research offers new hope for the treatment of Parkinson’s disease and other neurodegenerative diseases.
Source: Johns Hopkins Medicine
In studies of genetically engineered mice, Johns Hopkins Medicine researchers say they have identified a potentially new biological target involving Aplp1, a cell surface protein that drives the spread of the alpha-synuclein that causes Parkinson’s disease.
The results, published on May 31 in Natural communications, reveal how Aplp1 connects to Lag3, another cell surface receptor, in a key part of a process that helps spread harmful alpha-synuclein proteins to brain cells. These protein accumulations are characteristic of Parkinson’s disease.
Notably, researchers say, Lag3 is already the target of a combination cancer drug approved by the U.S. Food and Drug Administration (FDA) that uses antibodies to “teach” the human immune system what to do search and destroy.
“Now that we know how Aplp1 and Lag3 interact, we have a new way to understand how alpha-synuclein contributes to the progression of Parkinson’s disease,” says Xiaobo Mao, Ph.D., associate professor of neurology. at Johns Hopkins University. School of Medicine and member of the Institute for Cell Engineering.
“Our results 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 with Ted Dawson, MD, Ph.D., Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases at Johns Hopkins University School of Medicine and Director of the Johns Hopkins Institute for Cellular Engineering, Valina Dawson, Ph.D. and Hanseok Ko, Ph.D., professors of neurology at the School of Medicine and members of the Institute for Cellular Engineering.
Long-standing studies have shown that by clumping together and forming protein deposits, misfolded alpha-synuclein proteins travel from one brain cell to another, killing those responsible for producing a neurotransmitter called dopamine and causing progression of Parkinson’s disease via a type of “programmed transmission”. “cell death” that Johns Hopkins researchers have identified. The process, parthanatos (from the Greek word meaning “death”), results in disturbances in movement, emotional regulation, and thought.
Binding of Aplp1 with Lag3 on the cell surface allows healthy brain cells to take up roving clumps of alpha-synuclein, leading to cell death, the researchers say.
In mouse studies published in 2016 and 2021, Mao and Dawson’s team identified the role of Lag3 in binding to alpha-synuclein proteins, causing the spread of Parkinson’s disease. However, these studies indicated that another protein was partially responsible for the cell’s uptake of misfolded alpha-synuclein.
“Our work previously demonstrated that Lag3 was not the only cell surface protein that helped neurons take up alpha-synuclein. We therefore turned to Aplp1 in our most recent experiments,” explains Valina Dawson.
To determine whether Aplp1 was indeed contributing to the spread of harmful alpha-synuclein proteins, the researchers used a line of genetically modified mice lacking either Aplp1, Lag3, or both Aplp1 and Lag3. In mice lacking Aplp1 and Lag3, cellular uptake of the harmful alpha-synuclein protein dropped by 90%.
After injecting the Lag3 antibody into mice, they discovered that this drug also blocks the interaction of Aplp1 and Lag3, meaning that healthy brain cells can no longer take up disease-causing clumps of alpha-synuclein.
Researchers say the Lag3 antibody nivolumab/relatlimab, a drug approved by the FDA in 2022 for the treatment of cancer, may play a role in preventing cells from taking up alpha-synuclein.
“The anti-Lag3 antibody successfully prevented the spread of alpha-synuclein seeds in mouse models and showed better efficacy than Lag3 depletion due to the close association of Aplp1 with Lag3,” explains Ted Dawson.
This research has potential applications in treating other neurodegenerative diseases for which there is no cure, Mao says. In Alzheimer’s disease, which is associated with symptoms of memory loss, mood instability and muscle problems, tau proteins misfold and clump together in neurons at high levels, worsening disease. In Alzheimer’s research, Mao says scientists could try targeting Lag3 – which also binds to dementia-related tau protein – with the same antibody.
With the success of using the Lag3 antibody in mice, Ted Dawson says the next steps would be to conduct anti-Lag3 antibody trials in mice with Parkinson’s disease and Alzheimer’s disease . Johns Hopkins researchers are also studying how they might stop unhealthy cells from releasing disease-causing alpha-synuclein.
Other researchers participating in 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 of Johns Hopkins; Yasushi Shimoda of Nagaoka University of Technology; Martina Saar and Ulrike Muller from the University of Heidelberg; Creg Workman and Dario Vignali of the University of Pittsburgh School of Medicine and Cong Liu of the Chinese Academy of Sciences.
Funding: This work was supported by subsidies from the National Institutes of Health (R01NS107318, R01AG073291, R01AG071820, 1135 RF1NS125592, K01AG056841, R21NS125559, R01NS107404, P01AI1A1Ai144422) Kinson. , 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.
About this research news in neuropharmacology and Parkinson’s disease
Author: Alexandria Carolan
Source: Johns Hopkins Medicine
Contact: Alexandria Carolan – Johns Hopkins Medicine
Picture: Image is credited to Neuroscience News
Original research: Free access.
“Aplp1 interacts with Lag3 to facilitate pathological α-synuclein transmission” by Xiaobo Mao et al. Natural communications
Abstract
Aplp1 interacts with Lag3 to facilitate pathological α-synuclein transmission
Pathological α-synuclein (α-syn) spreads from cell to cell, in part through binding to the lymphocyte activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3, facilitating pathological α-syn binding, internalization, transmission, and toxicity.
Deletion of Aplp1 and Lag3 eliminates dopamine neuron loss and associated behavioral deficits induced by preformed α-syn fibrils (PFFs). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks α-syn PFF-induced neurodegeneration in vivo.
Identification of Aplp1 and interaction with Lag3 for PFF α-syn-induced pathology deepens our understanding of the molecular mechanisms of cell-to-cell transmission of pathological α-syn and provides additional targets for strategies Therapeutics aimed at preventing neurodegeneration in Parkinson’s disease and related diseases. α-synucleinopathies.