New findings from a study funded in part by The Michael J. Fox Foundation (MJFF) are drawing connections between genetics, inflammation and the gut in Parkinson’s. Deeper understanding of the relationship between these pathways can help researchers better define, measure, and treat disease.
Scientists are constantly learning more about Parkinson’s disease:
- Mutations in the LRRK2 gene are a leading genetic cause of Parkinson’s and cause higher levels of the LRRK2 protein, which are also found in people with the disease without a genetic connection.
- Patients also show higher levels of inflammation in the brain. Inflammation is the body’s natural response to fight off infection, but too much or chronic inflammation can be harmful.
- Finally, some have proposed that Parkinson’s starts outside the brain, accounting for changes in protein levels in the gut and olfactory bulb (responsible for smell) before motor symptoms begin.
A team of researchers from seven institutions across Canada — the Canadian LRRK2 in Inflammation Team (CLINT)— published findings that connected these three processes last month in the journal Science Translational Medicine.
They found that disease models with a LRRK2 mutation had a greater inflammatory response to a bacteria and virus, but they also showed higher markers of inflammation in the brain, even though the virus and bacteria were not seen there. This work shows a role for the LRRK2 protein in modulating inflammation, but also that too much of a good thing may be harmful. The question of how the systemic inflammation leads to brain inflammation remains to be answered.
CLINT’s finding builds evidence for the Parkinson’s process beginning outside the brain. The gut and the nasal passage are often entry points for harmful things, so inflammatory response there may be an early trigger of the disease.
Other studies have shown an association between LRRK2 and inflammation, but this study builds on how they may be connected and points to new measurement and treatment strategies.
"If this theory about LRRK2 is correct, it could open the door for the monitoring of infections as a key risk element for prediction, early detection and prevention of Parkinson's, and importantly, for new treatment approaches in general," said senior author Dr. Michael Schlossmacher of The Ottawa Hospital.
As overactive LRRK2 has also been found in people with Parkinson’s who do not have a LRRK2 mutation, targeting this pathway may help a broader patient population. In fact, drugs against LRRK2 are already in clinical trials in patients with and without the mutation. This finding may have implications for that work as well.
"Our research suggests that these drugs may well succeed in safely reducing excessive inflammation", said first author Dr. Bojan Shutinoski also of The Ottawa Hospital. "However, we should be careful not to abolish LRRK2 function altogether, as this could make people more susceptible to infections, in particular when being treated potentially for years."
Watch a webinar for more on the immune system’s role in Parkinson’s disease.