Progressive neurodegenerative disease affects more than 10 million people worldwide
Researchers at the Johns Hopkins University School of Medicine have discovered that cancer drugs may be able to target a protein that causes Parkinson’s disease (PD) by promoting the spreading of alpha-synuclein, a key hallmark of the neurological disease.
Published in Nature CommunicationsThe study revealed how the protein Aplp1 binds to Lag3, a cell surface receptor that allows the alpha-synuclein protein to spread to brain cells.
Currently one of the most common neurodegenerative disorders, Parkinson’s disease affects more than 10 million people worldwide and is characterized by progressive, disabling tremors, slowness of movements, and stiffness.
Previous research has already shown that misfolded alpha-synuclein protein travels from brain cell to brain cell, destroying cells responsible for producing the neurotransmitter dopamine and promoting the progression of Parkinson’s disease through programmed cell death.
The researchers used Bristol-Myers Squibb’s (BMS) Lag3 antibody drug Opdualag (nivolumab/relatolimab) to investigate whether Aplp1 contributes to the spreading of the α-synuclein protein using strains of genetically engineered mice lacking either Aplp1 or Lag3, or both.
Results showed that mice lacking Aplp1 and Lag3 had a 90% reduction in cellular uptake of harmful α-synuclein.
Moreover, injecting Lag3 antibodies blocked the interaction between Aplp1 and Lag3 in mice, preventing healthy brain cells from absorbing disease-causing clumps of α-synuclein.
BMS’s Opduralag, which is expected to be approved by the U.S. Food and Drug Administration in 2022 to treat adult patients with certain types of melanoma, may play a key role in preventing cells from absorbing alpha-synuclein.
“We now have a new way to understand how alpha-synuclein contributes to disease progression in Parkinson’s,” said Xiaobo Mao, associate professor of neurology at the Johns Hopkins University School of Medicine and member of the Institute for Cell Engineering.
“Our findings also suggest that targeting this interaction with drugs may be able to significantly slow the progression of Parkinson’s disease and other neurodegenerative diseases.”
The researchers are now investigating how to use the same antibody to target Alzheimer’s Lag3, which binds to the dementia-associated tau protein, and completely prevent unhealthy cells from releasing disease-causing alpha-synuclein.
