A gene mutation most commonly associated with Parkinson’s disease may also help the immune system destroy dangerous bacteria, according to research led by scientists at the University of Ottawa. The study focuses on the G2019S mutation in the LRRK2 gene, one of the most frequent genetic alterations linked to inherited Parkinson’s disease. While LRRK2 has been studied extensively in relation to neurons and neurodegeneration, the new findings indicate that it is also highly active in immune cells produced in the bone marrow. In particular, the mutation appears to strengthen the antibacterial activity of neutrophils, the white blood cells that form one of the body’s fastest defenses against invading microbes. The discovery adds an unexpected dimension to a gene better known for its role in movement disorders and suggests that its effects may extend across the nervous and immune systems.
The researchers examined how the LRRK2 G2019S mutation influences neutrophils, which are part of the innate immune system. Unlike adaptive immune cells, which learn to recognize specific pathogens over time, neutrophils respond rapidly to signs of infection. They migrate through the bloodstream toward damaged or infected tissue, engulf bacteria in a process called phagocytosis and expose the captured microbes to a range of destructive mechanisms. One of the most important is the production of reactive oxygen species, or ROS. These chemically reactive molecules can damage bacterial membranes, proteins and DNA after microbes have been enclosed inside a neutrophil. The new study found that neutrophils carrying the Parkinson’s-linked mutation generated substantially higher levels of ROS, giving them a greater capacity to eliminate bacteria living inside immune cells.
The researchers traced this effect to NADPH oxidase 2, an enzyme complex that acts as a molecular generator of reactive oxygen species. When activated, NADPH oxidase 2 transfers electrons to oxygen, producing molecules such as superoxide that can be converted into other antimicrobial oxidants. This oxidative burst is a central weapon used by neutrophils against engulfed bacteria. The G2019S form of LRRK2 appears to increase the activity of this system, effectively amplifying the oxidative response after a neutrophil encounters a pathogen. The result is not simply a higher level of immune-cell activation, but a specific biochemical change that improves the cells’ ability to create the hostile chemical environment required to kill intracellular bacteria. This mechanistic link helps explain why the mutation enhanced bacterial control in the experimental models.
To test the consequences of the mutation during infection, the team studied Salmonella Typhimurium, a bacterium capable of invading cells and causing serious disease. Salmonella can survive inside host cells by manipulating cellular processes that would normally destroy it. The researchers found that the pathogen produces a protein that suppresses the generation of reactive oxygen species, weakening one of the neutrophil’s most important antimicrobial defenses. By reducing the oxidative burst, Salmonella can improve its chances of remaining alive inside immune cells and may gain additional time to spread. Neutrophils carrying the LRRK2 mutation countered this strategy more effectively, producing stronger ROS responses and demonstrating superior control of the intracellular bacteria. The results reveal a direct molecular contest between a pathogen attempting to silence an immune defense and host cells equipped to intensify it.
This interaction illustrates what scientists often describe as an evolutionary arms race. Bacteria evolve proteins and secretion systems that interfere with immune signaling, alter cellular trafficking or neutralize toxic compounds. Hosts, in turn, develop genetic and biochemical mechanisms that detect infection and restore the ability to destroy invading organisms. A mutation that increases antibacterial activity could, under some circumstances, provide an advantage to individuals exposed to recurrent or severe infections. The researchers suggest that the persistence of LRRK2 variants in human populations may partly reflect this kind of evolutionary pressure, although the study does not establish that infection alone selected the mutation. Instead, the findings provide a plausible biological framework for understanding why a variant that can contribute to neurological disease might also influence host defense.
The apparent benefit comes with an important warning. Reactive oxygen species are powerful but indiscriminate molecules. They can damage pathogens, yet excessive or prolonged oxidative activity can injure healthy proteins, membranes and surrounding tissues. Neutrophils are essential for controlling acute infections, but their activation can also contribute to chronic inflammatory disorders when the response does not switch off appropriately. LRRK2 mutations have been associated with inflammatory conditions including Crohn’s disease and leprosy, although the precise role of the gene in these diseases remains unresolved. The new results suggest that increased LRRK2 activity could help explain how an immune response becomes more effective against bacteria while simultaneously increasing the risk of collateral tissue damage. In biological terms, the mutation may sharpen the immune system’s weapon without necessarily improving its ability to control when that weapon is used.
The findings may also contribute to a broader understanding of Parkinson’s disease. The G2019S mutation increases the kinase activity of LRRK2, an enzyme that modifies other proteins by adding phosphate groups. In neurons, altered LRRK2 signaling has been linked to cellular pathways involved in vesicle trafficking, organelle function and neurodegeneration. The new work shows that the same mutation can alter the behavior of neutrophils through NADPH oxidase 2 and oxidative metabolism. This raises the possibility that immune changes associated with LRRK2 could influence the environment in which neurodegenerative disease develops. Infections and inflammation can affect the brain through circulating immune signals, changes in the blood-brain barrier and activation of brain-resident immune cells. The study does not prove that bacterial infections cause Parkinson’s disease or that enhanced neutrophil activity directly damages neurons, but it provides a reason to investigate how peripheral immune responses may contribute to long-term changes in vulnerable brain regions.
The therapeutic implications are potentially significant, although they remain at an early research stage. Current strategies aimed at LRRK2 often focus on reducing its activity because excessive signaling has been implicated in Parkinson’s disease and other disorders. The new findings indicate that indiscriminate suppression could also weaken an important antibacterial pathway. A future treatment might therefore need to modulate LRRK2 with much greater precision, limiting harmful signaling in specific tissues while preserving or carefully adjusting its function in immune cells. Similar approaches could be used to regulate NADPH oxidase 2 or the oxidative burst itself. The objective would not be to simply turn immunity up or down, but to maintain enough ROS production to eliminate microbes while preventing the persistent oxidative stress that promotes inflammation. Such therapies would require careful testing because neutrophil function is essential for protection against a wide range of infections.
The University of Ottawa team plans to examine how other LRRK2 mutations affect immune responses and disease progression. Different genetic variants may alter the protein in distinct ways, producing immune effects that cannot be predicted from the G2019S mutation alone. Future research may also investigate whether repeated infections create lasting changes in the brain or immune system of people carrying LRRK2 variants. For now, the study presents a striking example of how a gene associated with one disease can influence an entirely different biological system. By showing that the Parkinson’s-linked mutation increases NADPH oxidase 2 activity in neutrophils and improves control of intracellular Salmonella, the research connects neurodegeneration, innate immunity and microbial survival in a single molecular story. It also reinforces a central principle of immunology: the strongest defense is not always the safest one, and health depends on keeping both sides of that equation in balance.
Subject of Research: Animals
Article Title: The Parkinson’s disease-linked G2019S mutation of LRRK2 increases NADPH oxidase-2 activity in neutrophils for superior control of bacterial infections
Web References: https://www.uottawa.ca/faculty-medicine/ ; https://www.nature.com/articles/s41423-026-01451-6
References: Cellular and Molecular Immunology, DOI: 10.1038/s41423-026-01451-6
Image Credits: Faculty of Medicine, University of Ottawa
Keywords: LRRK2, G2019S mutation, Parkinson’s disease, neutrophils, innate immunity, reactive oxygen species, NADPH oxidase 2, bacterial infections, Salmonella Typhimurium, inflammation
