Gut Immune Response Seen to Protect Dopamine Neurons in Study in Roundworms

Immune reactions, originating in the gut, protect neurons from the damage or death associated with Parkinson’s disease by keeping a check on the mitochondrial health of these nerve cells — at least in the brains of roundworms.

The study, “The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective,” published in the journal Cell Reports, suggests that the immune system constantly keeps an eye on mitochondria, removing them when they become a burden for the cell.

Plenty of evidence shows that, in Parkinson’s disease, faulty mitochondria contribute to the degeneration of dopamine neurons. A compound that has been linked to the disease in humans, and has been used to model Parkinson’s in animals, is a pesticide called rotenone.

The compound is known to block the activity of mitochondria by preventing the proper function of complex I — the first in a series of energy-producing protein clusters inside the mitochondria. To investigate if there is an immune component impacting its effect on neurodegeneration, researchers at the University of Iowa treated roundworms with rotenone.

For reasons that have so far eluded scientists, dopamine neurons in roundworms tend to be quite sensitive to the effects of a flawed mitochondrial complex I, and die earlier than other cells when exposed to compounds such as rotenone.

But when researchers treated hundreds of roundworms with rotenone, only 7 percent of them, on average, lost neurons, indicating that a protective mechanism was at work.

An in-depth analysis revealed that rotenone triggered several molecular immune pathways when mitochondria stopped working. Inactivating these immune responses one by one allowed the team to home in on a specific pathway. When this pathway, called p38MAPK, was turned off, more neurons died.

Interestingly, the research team noted that the immune pathway was activated only in the gut of the worms, and not in the nervous system.

“We think somehow the gut is protecting neurons,” Veena Prahlad, assistant professor in biology at the University of Iowa, said in a news release. “If we can understand how this is done in the roundworm, we can understand how this may happen in mammals.”

The team discovered that the p38MAPK pathway, in turn, activated mechanisms doing away with faulty mitochondria, which researchers believe is neuroprotective.

“How it’s happening is suggestive of the possibility that the innate immune response is constantly checking its mitochondria,” Prahlad said.