Researchers report that they have identified a protein that enables a toxic natural aggregate to spread from cell to cell in a mammal’s brain — and a way to block that protein’s action. Their study in mice and cultured cells suggests that an immunotherapy already in clinical trials as a cancer therapy should also be tested as a way to slow the progress of Parkinson’s disease, the researchers say.
A report on the study appears in the journal Science.
According to the researchers, the new findings hinge on how aggregates of α-synuclein protein enter brain cells. Abnormal clumps of α-synuclein protein are often found in autopsies of people with Parkinson’s disease and are thought to cause the death of dopamine-producing brain cells.
A few years ago, the researchers say, a researcher in Germany published evidence for a novel theory that Parkinson’s disease progresses as α-synuclein aggregates spread from brain cell to brain cell, inducing previously normal α-synuclein protein to aggregate, and gradually move from the “lower” brain structures responsible for movement and basic functions to “higher” areas associated with processes like memory and reasoning. Intrigued, the researchers began working to investigate how the aggregates enter cells.
The researchers knew they were looking for a certain kind of protein called a transmembrane receptor. They first found a type of cell α-synuclein aggregates could not enter — a line of human brain cancer cells grown in the laboratory. The next step was to add genes for transmembrane receptors one by one to the cells and see whether any of them allowed the aggregates in. Three of the proteins did, and one, LAG3, had a heavy preference for latching on to α-synuclein aggregates over nonclumped α-synuclein.
The team next bred mice that lacked the gene for LAG3 and injected them with α-synuclein aggregates. “Typical mice develop Parkinson’s-like symptoms soon after they’re injected, and within six months, half of their dopamine-making neurons die,” said Ted Dawson, one of the study’s leaders. “But mice without LAG3 were almost completely protected from these effects.” Antibodies that blocked LAG3 had similar protective effects in cultured neurons, the researchers found.
The researchers note that antibodies targeting LAG3 are already in clinical trials to test whether they can beef up the immune system during chemotherapy. If those trials demonstrate the drugs’ safety, the process of testing them as therapeutics for Parkinsons’ disease might be sped up, they say.
For now, the research team is planning to continue testing LAG3 antibodies in mice and to further explore LAG3’s function.
Paper: “Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3”
Reprinted from materials provided by Johns Hopkins University.