Patients with inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, are at higher risk of Parkinson’s. Researchers have now uncovered why, says Professor Veerle Baekelandt, who heads the Neurobiology and Gene Therapy Research Group, where the study took place.

Parkinson’s is, after Alzheimer’s, the most common neurodegenerative disorder. The disease is best known for the trembling and stiffness associated with it, but Parkinson’s can also bring about cognitive decline and mood and anxiety symptoms. These symptoms can be suppressed with medication. Over time, however, medications can prove inadequate, or the side effects become too severe, says Professor Baekelandt. “We therefore continue to search for the mechanisms behind Parkinson’s, hoping to one day find a cure for the disease.”

The last 20 years have seen enormous advances in research: “We used to be completely in the dark about the cause of Parkinson’s disease. Since then, a number of hereditary forms have been found, and we now have a better understanding of the condition. Once the concrete cause for one particular form is known, it becomes much easier to uncover the disease mechanism in general. And then the next step is to look for medication that addresses the cause, hopefully impeding the disease or even curing it.”

One target of Professor Baekelandt’s research group is the genetic mutation responsible for the most common hereditary form of Parkinson’s disease. For some time now it has been known that this mutation is also found in people with inflammatory bowel diseases. This should not come as a great surprise, according to Professor Baekelandt: “There have long been indications of a possible link between Parkinson’s and intestinal problems. We know that in Parkinson’s, many of the changes occur outside the brain — including in the intestines. Constipation is often one of the early symptoms in Parkinson’s patients.”

In addition, epidemiological studies have recently shown that people with inflammatory bowel disease are more likely to develop Parkinson’s than others. But why this is so was not yet clear.

The gene in which the ‘Parkinson’s mutation’ is found causes the protein Leucine Rich Repeat Kinase 2 (LRRK2) to become hyperactive, explains Professor Baekelandt. To find out whether this mechanism also plays a role in inflammatory bowel disease, the researchers studied mice with the same mutation: “Are they indeed more prone to intestinal inflammation? To find out, we administered a substance to them that stimulates the intestines. In other words, we mimicked an inflammation in the gut — and we saw that the mice with a mutation reacted much more strongly to it than our control mice. This means that the mutation does indeed make the mice more susceptible to developing inflammatory bowel disease. When we gave the mice a drug that inhibited LRRK2, we saw an associated reduction in intestinal inflammation.”

Moreover, in mice that developed intestinal inflammation, the researchers also saw an effect in the brain. “They did not immediately develop Parkinson’s — not surprising, as that’s a disease of old age. But an inflammatory response occurred in the brain, and when we tried to induce Parkinson’s symptoms, we saw that the mice with the mutation showed those symptoms much more quickly and much more severely.”

The researchers were also able to show that the immune system plays an important role in all this: “Strikingly, the ‘Parkinson’s mutation’ is found primarily in immune cells, both in people with inflammatory bowel disease and those with Parkinson’s, and less in brain cells. To clarify this, we replaced immune cells from mice with the mutation with immune cells from mice without the mutation via bone marrow transplantation. That proved sufficient to eliminate the symptoms in the intestines. Our suspicion is that the mutated immune cells are the link between the gastrointestinal system and the brain. We think that when inflammation persists in the colon, these cells infiltrate the brain and contribute to an inflammatory response there, resulting in neurodegeneration. It would also immediately explain why patients treated for inflammatory bowel disease are less likely to develop Parkinson’s. These findings offer a new perspective on Parkinson’s disease, with, of course, also implications for the search for a therapy.”

Several clinical trials in Parkinson’s patients are currently underway with agents that inhibit LRRK2 activity, says Professor Baekelandt. “It currently represents one of the most promising avenues in the search for a drug Our results show that this could also help people with inflammatory bowel disease.” (ivh)