What causes the death of neurons in Parkinson’s disease is still unknown. A recent study from Columbia University researchers suggests that neurons may be mistaken for alien intruders and attacked by the person’s own immune system. This would be similar to the way autoimmune diseases such as celiac disease, type I diabetes, and multiple sclerosis attack the body’s cells.
The new proposition about Parkinson’s surfaces from other findings in the study that goes against a long held assumption about neurons and the immune system.
“This is a new, and likely controversial, idea in Parkinson’s disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson’s that resemble treatments for autoimmune diseases,” said the study’s senior author, David Sulzer, PhD.
Neurobiologists have believed for decades that neurons are protected from attacks from the immune system. One of the reasons is that they do not show antigens on their cell surfaces.
Most cell types, when infected by virus or bacteria, will display bits of the microbe, known as antigens, on their outer shell. When the immune system recognizes the foreign antigens, T cells attack and kill the cells. Because scientists thought that neurons did not display antigens, they also thought that the neurons were free from T-cell attacks.
“That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system,” Dr. Sulzer said. “But, unexpectedly, we found that some types of neurons can display antigens.”
Major Histocompatibility Complexes
Special proteins called Major Histocompatibility Complexes (MHCs) are involved in cells display of antigens. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors, Dr. Sulzer noticed that MHC-1 proteins were present in two types of neurons. These two types of neurons, one of which is dopamine neurons in a brain region called the substantia nigra, degenerate during Parkinson’s disease.
To see if living neurons use MHC-1 to display antigens (and not for some other purpose), Drs. Sulzer and Cebrián conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells.
The studies showed that under certain circumstances, including conditions known to occur in Parkinson’s, the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson’s were much more responsive than other neurons to signals that triggered antigen display.
Parkinsons T Cells
Researchers then verified that T cells did in fact recognize and attack neurons displaying specific antigens.
The results hint that Parkinson’s is partially an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea.
“Right now, we’ve showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons,” Dr. Sulzer says, “but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson’s patients that can attack their neurons.”
Dr. Sulzer emphasizes that even if the immune system does kill neurons in Parkinson’s disease, that it is not the only thing going awry in the disease.
“This idea may explain the final step,” he says. “We don’t know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not.”
Carolina Cebrián, Fabio A. Zucca, Pierluigi Mauri, Julius A. Steinbeck, Lorenz Studer, Clemens R. Scherzer, Ellen Kanter, Sadna Budhu, Jonathan Mandelbaum, Jean P. Vonsattel, Luigi Zecca, John D. Loike, David Sulzer.
MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration.
Nature Communications, 2014; 5 DOI: 10.1038/ncomms4633
Image courtesy of Carolina Cebrian.