A team of scientists has discovered that an immune mechanism that clears bacterial infections may also play a role in causing Parkinson's disease. The findings clarify the role of the protein LRRK2 in tuberculosis, suggesting that it behaves similarly in Parkinson's. This new insight could pave the way for improved treatments for both diseases.
Mutations in the LRRK2 gene have been fingered in a range of diseases, including Crohn's, ulcerative colitis and leprosy, in addition to tuberculosis (TB) and Parkinson's. And while an LRRK2 mutation is common in Parkinson's patients and LRRK2 blockers are showing promise against it, just how the mutation causes disease is poorly understood.
Researchers from the Francis Crick Institute, GlaxoSmithKline and Newcastle University studied LRRK2 in human and mouse macrophages—immune cells that seek and destroy bacteria. The macrophages were infected with Mycobacterium tuberculosis (Mtb). Combining genetic, pharmacological and proteomics approaches, they found that LRRK2 prevents a crucial step in eliminating bacteria.
Blocking or deleting LRRK2 in the macrophages remedied this and reduced levels of Mtb. Knocking out the LRRK2 gene in mice worked similarly—treated mice mounted a better early immune response to TB infection and had less Mtb in their lungs up to two weeks after infection, compared to control mice. The study appears in the EMBO Journal.
The findings might explain how LRRK2 inhibitors, such as those in development at Denali, could treat Parkinson's. "We think that this mechanism might also be at play in Parkinson's disease, where abnormal masses of protein called 'Lewy bodies' build up in neurons in the brain and cause damage," said Susanne Herbst, joint first author of the paper and post-doctoral fellow at the Crick Institute, in a press release.
This insight could shift the focus in Parkinson's research for the better: "The dogma in the Parkinson's field has been to focus almost exclusively on what is happening to neurons in the brain to make them degenerate," said co-author Patrick Lewis, an associate professor in cellular and molecular neuroscience at the University of Reading, in the statement. "This study reinforces why we should think more broadly about the events that cause neurodegeneration, and that some of the answers to Parkinson's disease might come from immunology,"
LRRK2 drugs developed for Parkinson's could be repurposed for TB, said Max Gutierrez, Group Leader at the Crick. With drug-resistant TB on the rise and Bacille-Calmette-Guérin (BCG), the only WHO-approved TB vaccine, showing variable efficacy in adults, there is always room for new treatments. For example, a new antibiotic discovered in Italian soil could come in handy against bacteria that have become resistant to rifampin, a first-line drug used to treat TB.
"LRRK2 inhibiting drugs are already being developed to treat Parkinson's disease and we're trying to see if we can repurpose them as a potential new TB therapy. This should be relatively straightforward because TB infects the lungs, so the LRRK2 inhibitors wouldn't need to cross the blood-brain barrier like they do in Parkinson's disease," Gutierrez said.