Researchers have discovered a way to block the spread of alpha-synuclein between neurons, which is believed to be at the core of the progression of the neurodegeneration seen in people with Parkinson’s disease.
Interestingly, the drug that was able to block the spread and prevent neuron death is currently in clinical trials as a cancer immunotherapy.
The study, “Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3,” was published in the prestigeous journal Science. It emphasized that if the trials prove the drug is safe, the path to testing it in patients with Parkinson’s disease may be relatively short.
Researchers at Johns Hopkins University School of Medicine in Baltimore have been working to understand how alpha-synuclein spreads between nerve cells ever since evidence emerged that faulty, aggregated forms of the protein also could trigger the aggregation of alpha-synuclein in neighboring cells.
This spread of misfolded protein aggregates reminded researchers of how prions could cause previously normal proteins to “turn bad.” Studies have shown that such aggregates spread from the lower regions of the brain — holding dopamine neurons that control movement — to the outer regions that control cognitive functions such as memory. The neurodegeneration of neurons follows in the wake of alpha-synuclein clumping.
Ted Dawson, MD, PhD, director of the Institute for Cell Engineering at Johns Hopkins, engaged fellow researchers Valina Dawson, PhD, professor of neurology, and Han Seok Ko, PhD, assistant professor of neurology, to explore how alpha-synuclein aggregates could leave one cell and enter another. The researchers believed that finding could be key to stopping the propagation of alpha-synuclein clumping.
Earlier studies have hinted that a process called endocytosis may be involved. Endocytosis is a common way for cells to transport molecules across the cell membrane by engulfing the molecule in a part of the cell membrane. The membrane forms a vesicle that is released into the cell holding the molecule. The process resembles the movement of bubbles reaching the surface in a carbonated drink, but reversed.
For the endocytosis process to be initiated, a molecule needs to bind to a specific receptor, acting as the key to unlock the door into the cell.
Using a type of cancer cells that were inherently resistant to the spread of alpha-synuclein, the research team started the meticulous work of adding genes, one by one, coding for receptors known to be used as endocytosis locks.
They tested a total of 352 receptor genes, and found that three of them would bind alpha-synuclein. One of the identified factors, called LAG3 (lymphocyte-activation gene 3), bound alpha-synuclein aggregates strongly while not binding unaggregated forms of the protein.
To confirm if LAG3 was crucial for the spread of clumped alpha-synuclein, the team bred mice that lacked the receptor, and injected them with clumps of alpha-synuclein. Such injections usually are devastating for mice.
“Typical mice develop Parkinson’s-like symptoms soon after they’re injected, and within six months, half of their dopamine-making neurons die,” Ted Dawson, senior author of the study, said in a press release. “But mice without LAG3 were almost completely protected from these effects.”
Without LAG3, clumped alpha-synuclein could not spread between cells as in normal mice, and as a consequence, brain cells did not die.
Likewise, when the team treated neurons, grown in the lab, with antibodies preventing alpha-synuclein binding to LAG3, they could not trigger the fast spread and toxic effects normally seen when cells are exposed to clumped alpha-synuclein.
“It was a pretty dramatic effect we saw,” Ted Dawson told Parkinson’s News Today, noting that it seemed potent enough to be seen as a potential treatment for slowing or preventing progression of Parkinson’s disease.
Several clinical trials are testing antibodies blocking LAG3 as cancer immunotherapy. Ted Dawson said he has initiated discussions with potential sponsors about testing such antibodies in Parkinson’s patients. He envisions such a treatment could benefit patients ranging from pre-smptomatic, up to mid-stage disease.
“We are really excited and optimistic about the findings,” Ted Dawson told Parkinson’s News Today. “I think our findings can immediately move into patients, since there are really good LAG3 therapeutics already tested in cancer patients.”
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