A protein called Aplp1 is now on the radar for its ability to spread material in the brain that may be responsible for Parkinson’s disease. Another protein, Lag3, interacts with Aplp1, blocking the spread in mice. The researchers were then made aware that the Lag3 protein is a target in a combination therapy for cancer that has already been US Food and Drug Administration (FDA) approved.
According to a report by the Johns Hopkins Newsroom, an international group of scientists produced a paper describing how these two proteins, when combined, enable harmful alpha-synuclein clumps to enter the brain cells.
Xiaobo Mao, Johns Hopkins neuroscientist, commented that clarifying Lag3 and Aplp1’s interaction gives the researchers new insight into alpha-synuclein’s contribution to Parkinson’s disease progression.
Lag3 and Aplp1’s Interaction
Dr. Mao further stated that targeting Lag3 and Aplp1’s interaction with drugs may have the beneficial effect of slowing Parkinson’s as well as other neurodegenerative diseases.
About Parkinson’s Disease
Well over eight million individuals worldwide have been diagnosed with Parkinson’s, a neurodegenerative disease. Parkinson’s is usually diagnosed after symptom’s become obvious such as tremors, balance problems, and mental health issues. The disease is currently incurable. A region in the brain involved with fine motor control is called the substantia nigra. Parkinson’s symptoms are believed to be the result of impairment or death of dopamine-producing neurons in the substantia nigra. Researchers have been investigating mysterious clumps in the brains of Parkinson’s patients for several decades and are now putting the pieces of these puzzles together.
Lewy Bodies are Abnormal Clumps of Protein
Lewy Bodies consist of abnormal clumps of protein, most of which are misfolded alpha-synuclein travelling between neurons. Typically, alpha-synuclein is responsible for the steady communication flow between neurons but it malfunctions when it becomes insoluble and misfolded. Investigators have not been able to determine whether these symptoms cause the disease or if they are a symptom of the disease.
About Lag3
Previous studies using mouse models determined that Lag3 binds to alpha-synuclein proteins while spreading Parkinson’s disease pathology in neurons. This was a significant clue to researchers that another protein was responsible for neurons and swept up misfolded alpha-synuclein proteins.
The researchers turned their attention to Aplp1 in their recent experiments according to Valina Dawson, neuroscientist at Johns Hopkins. The tests consisted of mice that were genetically modified and missing either Lag3, Aplp1, or both. A major difference occurred when each of the proteins helped brain cells absorb alpha-synuclein independently. On the contrary, both proteins working together created a significant increase in absorption of harmful alpha-synuclein. In other words, a larger amount of alpha-synuclein was absorbed into healthy brain cells when both proteins were missing as compared to just one protein being deleted.
About the Drug
Normal mice were given the drug nivolumab/relatlimab which is a melanoma medication containing the Lag3 antibody. They discovered that it prevented interaction between Laa3 and Aplp1, almost entirely blocking alpha-synuclein clumps in neurons. Johns Hopkins Neuroscientist Ted Dawson said that the anti-Lag3 prevented the spread of alpha-synuclein seeds and prevented better efficacy than Lag3 depletion due to Aplp1’s association with Lag3. Plans are in progress to test the Lag3 antibody where research has indicated Lag3 to also be a potential target.
Research has been published in Nature Communications.
