Scientists Sharpen Focus Into Genetic Link to Parkinson Inflammation

Canadian researchers think mutations in 1 gene are likely responsible for an increased risk of Parkinson disease (PD), as well as Crohn and leprosy, according to results of an animal study published this week in Science Translational Medicine.

The leucine-rich repeat kinase-2 (LRRK2) gene has been linked with PD, leprosy, and Crohn, which all share inflammation as a common factor. LRRK2 is mutated in about 2% of patients with PD.

Researchers wanted to test if LRRK2 mitigates inflammation arising after infections; they found that in mice carrying different versions of LRRK2, LRRK2 altered the course of bacterial and viral infections by modulating inflammation. The mutation, called p.G2019S, increases the activity of the LRRK2 protein.

In the first part of the study, adult mice were intravenously inoculated with Salmonella typhimurium, resulting in sepsis. Scientists also induced encephalitis in newborn mouse pups that were intranasally infected with reovirus (serotype 3 Dearing).

Mice with the mutation had a stronger inflammatory response to both bacteria and viruses. During viral encephalitis, the p.G2019S LRRK2 mutation worsened survival in mice, more so in females. Animals with viral encephalitis expressing a variant that blocked LRRK2's enzyme function showed improved survival. Mice expressing 1 or 2 p.D1994S Lrrk2 alleles showed lower mortality from reovirus-induced encephalitis. Reovirus-infected brains from mice expressing the p.G2019S mutant LRRK2 contained higher concentrations of α-synuclein.

In both mouse models, wild-type LRRK2 expression was protective and showed a sex effect, with female LRRK2-deficient animals not controlling infection as well as males.

LRRK2 may modulate the course of microbial infections in a manner that depends on mouse genotype, sex, and the type of pathogen. Thus, LRRK2 alleles may alter the course of microbial infections by modulating inflammation, and this may be dependent on the sex and genotype of the host as well as the type of pathogen.

The researchers looked at several markers of inflammation, including oxidative stress.The inflammatory response could spill over into the brain, even when the infection itself never reached the brain.

"Everyone thought that LRRK2's primary role was in the brain, because of its association with Parkinson's disease. But our research shows for the first time that its primary role is probably in the immune system," senior author Michael Schlossmacher, MD, Bhargava Family Research Chair in Neurodegeneration, director of neuroscience and a neurologist at The Ottawa Hospital, and professor at the University of Ottawa Brain and Mind Research Institute, said in a statement.

"Our research suggests that certain mutations in LRRK2 enhance inflammation and help the body to defend itself better against viruses and bacteria, but this enhanced inflammation could also increase the risk of Parkinson's and other brain diseases," he added.

This new research supports a theory which suggests that PD may start outside the brain, in organs like the nose and the gut, which are on the front line of invasion by microbes and thus, sites of inflammation.

"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," Schlossmacher said.