Toxic aggregates of the alpha-synuclein protein, which are known to cause Parkinson’s disease, can spread from one brain cell to the other, causing the disease to progress. In a new study, researchers have identified a protein that allows this mechanism to occur, posing itself as a target to stop the progression of the disease.
The study, “Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3,” published in Science, suggests that an immunotherapy already in clinical trials could be tested as a way to slow the progression of Parkinson’s disease.
Abnormal aggregates of alpha-synuclein in the brain tissue are believed to be one of the causes of brain cells’ death.
Previous work suggested that Parkinson’s disease progression was due to the spread of alpha-synuclein aggregates from one brain cell to another, explaining how brain areas responsible for memory and reasoning, and not only those responsible for movement and basic functions, also became affected as the disease progresses.
To target this process, Dr. Ted Dawson, MD, PhD, director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, teamed up with Valina Dawson, PhD, professor of neurology, and Han Seok Ko, PhD, assistant professor of neurology, to investigate how the alpha-synuclein aggregates could enter cells.
The researchers identified a type of human brain cancer cells, grown in the laboratory, that did not allow alpha-synuclein aggregates to enter. More careful analyses showed that these cells were lacking three specific transmembrane proteins. These proteins are typically found on the outside of cells and are responsible for admitting specific proteins inside cells. One of the identified transmembrane proteins, called LAG3, showed a particular preference for alpha-synuclein aggregates over nonclumped alpha-synuclein.
Since the absence of LAG3 in the brain cells of Parkinson’s disease animal models protected the mice from the effects of alpha-synuclein aggregates, the researchers proceeded to investigate whether LAG3 blocking therapies could be used to prevent these aggregates to spread.
Importantly, the investigators found that these LAG3 blocking therapies could also prevent the spreading of alpha-synuclein aggregates in cultured neurons, revealing that LAG3 inhibitors may also be a promising therapeutic approach for Parkinson’s patients.
LAG3 inhibitors, which have recently emerged as promising immune checkpoint inhibitors that may be better alternatives or work in synergy with currently approved checkpoint inhibitors, are currently in clinical trials for a variety of solid and hematologic tumors. If the ongoing clinical trials demonstrate the drugs’ safety, the process of testing them as therapeutics for Parkinson’s disease might be sped up, Dawson said.
“We were excited to find not only how alpha-synuclein aggregates spread through the brain, but also that their progress could be blocked by existing antibodies,” says Xiaobo Mao, PhD, first author on the study. Nevertheless, more studies on LAG3 function are required.
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