Blocking a newly-found mediator may slow Parkinson's disease

By John Murphy, MDLinx
Published October 4, 2016

Key Takeaways

Researchers have identified how a pathologic protein associated with Parkinson’s disease spreads from neuron to neuron and accumulates in the brain. When researchers shut down this newly-found mediator—the protein LAG3—they found that the pathologic protein α-synuclein accumulated much slower in the neurons of mice, and neuronal destruction and behavioral deficits were greatly delayed as well.

This finding provides a potential target for new therapies that could slow the progression of Parkinson’s disease, the authors concluded in their September 30, 2016 article in Science.

Emerging research indicates that the spread of pathologic α-synuclein may be a primary driver of Parkinson’s disease, but until now no one knew exactly how α-synuclein is transmitted from neuron to neuron. This study showed that α-synuclein does this by binding to another protein, lymphocyte-activation gene 3, or LAG3.

“The identification of LAG3 as a mediator in transmitting abnormal α-synuclein between neurons provides both insight into the disease mechanism and a potential therapeutic target for the disease,” said Beth-Anne Sieber, PhD, a program director at the National Institute of Neurological Disorders and Stroke (NINDS), in Bethesda, MD, which partially funded the research.

“In looking for ways to slow the progression of Parkinson’s disease, we were interested to see how abnormal α-synuclein enters neurons. Therefore, we began by looking for proteins that would be involved in that process,” said the study’s senior author Ted M. Dawson, MD, PhD, Professor of Neurodegenerative Diseases and Director of the Institute for Cell Engineering at Johns Hopkins University, in Baltimore, MD.

To that end, Dr. Dawson and colleagues screened a library of transmembrane proteins to see if any would bind to abnormal α-synuclein preformed fibrils. Of the three proteins they found, only LAG3 was specific for the abnormal α-synuclein.

To confirm the role of LAG3, the researchers first deleted the LAG3 gene in mice, and then injected α-synuclein fibrils in these mice and in normal mice. The normal mice quickly developed Parkinson’s disease-like symptoms, including motor deficits, loss of grip strength, and the eventual death of dopamine neurons. But the mice lacking LAG3 demonstrated normal grip strength and motion, and had no significant loss of dopamine neurons.

The researchers also compared neurons that had been removed from both types of mice and grown in culture. When the investigators added α-synuclein fibrils to normal neurons, the α-synuclein fibrils were quickly pulled into the cells and passed along to neighboring cells; however, this occurred in very few neurons from the mice that lacked the LAG3 gene.

“We knew from these experiments that LAG3 was important for the neurons’ ability to take up α-synuclein fibrils,” Dr. Dawson said. “Antibodies that block the activity of LAG3 are being tested in clinical trials as a form of cancer immunotherapy. We were therefore curious to see whether we could use similar antibodies to block the function of LAG3.”

When the researchers tested this, they found that neurons treated with antibodies acted similarly to the neurons in LAG3 knockout mice. Cell-to-cell transmission of α-synuclein fibrils was reduced in both types of neurons. These results suggest that antibodies can block LAG3 function, providing a potential way to slow or even stop the progression of Parkinson’s disease.

Currently, the researchers are testing the LAG3 antibodies in animal models of Parkinson’s disease to further investigate their possible therapeutic and protective effects against disease progression.

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