Although it may be protective against infections, a specific mutation in the LRRK2 gene — the gene linked to most inheritable mutations that can cause Parkinson’s disease — may increase Parkinson’s risk by promoting inflammation in the brain, according to new research.
The study, “Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner,” appeared in the journal Science Translational Medicine.
Mutations in the LRRK2 gene are found in about 2% of people with Parkinson’s, with different studies reporting a greater frequency in women. But a mutated LRRK2 also has been associated with greater risk for two other disorders in which inflammation is a key component: Crohn’s disease (CD), which targets the gut, and leprosy, which affects the peripheral nervous system.
LRRK2 is highly expressed in several types of immune cells, including macrophages and natural killer cells. This suggests it plays a role in innate immunity — nonspecific defense mechanisms prompted by any given microbe.
To test this hypothesis, a team from Canada assessed LRRK2 expression in human white blood cells and tissues during inflammation, and studied viral and bacterial infections in Lrrk2 mutant animals.
First, the team found that neutrophils — immune cells that travel to the site of an infection — were the cell type with the highest expression of LRRK2 in healthy participants. Immune–related tissues, such as the bone marrow and lymph nodes, showed abundant RNA levels of LRRK2. RNA is the genetic template that gives origin to proteins.
Then, the investigators found significant protein production in gut samples of patients with Crohn’s disease, and in brain tissue of people infected by HIV, rabies virus, or virally infected peripheral nerve roots. All of these are characterized by inflammation.
Taking this data together with findings in Parkinson’s patients, which showed strong LRRK2 production in brain white blood cells, the team “concluded that LRRK2 appears to be abundant in infiltrating leukocytes of human tissues during acute or chronic inflammation.”
In mice, the researchers used a sepsis model — inoculation with Salmonella typhimurium — and an encephalitis model, induced by infection with reovirus, to assess the role of LRRK2 in acute bacterial and viral infection.
They found that, in both models, normal (wild-type) Lrrk2 expression was protective compared with complete Lrrk2 absence or production from only one gene copy. Female mice lacking Lrrk2 showed a stronger inflammatory response than male animals that lacked the gene, the researchers noted.
Then, the scientists studied the p.G2019S mutation — the most common mutation in LRRK2 — which increases the activity of the LRRK2 protein. Carrying this mutation enhanced inflammation and boosted the protective effect of normal Lrrk2, with reduced bacterial growth and longer survival during sepsis. This greater protection was mediated by the higher number of myeloid cells — monocytes, macrophages and neutrophils — in the spleen.
In mice with sepsis and with the Lrrk2 mutation, the scientists also observed increased oxidative damage in the spleen and the brain.
“When mice with the Parkinson’s-linked mutation were infected with Salmonella bacteria, we saw very high levels of oxidative stress in the brain, almost twice as high as in normal mice,” Bojan Shutinoski, PhD, the study’s first author, said in a press release. “This was particularly surprising because the bacteria never even entered their nervous system!”
Mouse pups with encephalitis and no Lrrk2 had increased mortality — especially females — and increased activation of microglia, the resident immune cells of the brain. Animals with the p.G2019S mutation showed reduced survival despite lower viral levels. These mice also exhibited greater brain infiltration of white blood cells, and higher concentrations of the alpha-synuclein protein — the main component of Parkinson’s hallmark Lewy bodies.
The higher mortality in mice with the p.G2019S mutation was likely due to increased enzymatic activity of Lrrk2, as animals with a mutation (p.D1994S) that suppresses this activity showed greater survival.
“Our findings support a growing body of evidence that the LRRK2 protein functions in immune cells both within the brain … and the periphery,” the investigators said.
“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,” said Michael Schlossmacher, MD, the study’s senior author and a neurologist at The Ottawa Hospital.
“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,” added Schlossmacher, also a professor at the University of Ottawa Brain and Mind Research Institute.
“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.
The results also may have implications for the clinical development of therapies that block LRRK2 activity.
“Our research suggests that these drugs may well succeed in safely reducing excessive inflammation,” Shutinoski said. “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.”
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