Six degrees of separation is an early 20th-century philosophy that all living things are inextricably linked in not such distant ways. While social media and network theory has added new life to the abstract concept in recent years, close connections in the realm of biology have remained more enigmatic. Yet now, new evidence from investigators at the Francis Crick Institute, Newcastle University, and GlaxoSmithKline have found a connection between two seemingly disparate diseases: Parkinson’s and tuberculosis (TB). Findings from the new study—published online today in The EMBO Journal, an article entitled “LRRK2 Is a Negative Regulator of Mycobacterium tuberculosis Phagosome Maturation in Macrophages”—provide a possible explanation of the cause of Parkinson's disease and suggest that drugs designed to treat Parkinson's might work for TB too.

The most common genetic mutation in Parkinson's disease patients is in a gene called LRRK2, which makes the LRRK2 protein overactive. Moreover, drugs that block LRRK2 are a promising new treatment for Parkinson's, with many pharmaceutical companies developing drugs to target LRRK2 and clinical trials underway. But how overactive LRRK2 causes Parkinson's and why LRRK2 blockers work was a mystery.

“Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, chronic inflammation, and mycobacterial infections,” the authors wrote. “Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown.”

Image of a macrophage labeled for the nucleus (blue), fused lysosomes and phagosomes (red), and TB bacteria (green). [Susanne Herbst/Francis Crick Institute]
Image of a macrophage labeled for the nucleus (blue), fused lysosomes and phagosomes (red), and TB bacteria (green). [Susanne Herbst/Francis Crick Institute]

By studying what LRRK2 does within macrophages that are infected with Mycobacterium tuberculosis (Mtb)—the bacterium that causes TB— the research team believes they have uncovered a potential cause of Parkinson's. Macrophages recognize and engulf Mtb, securing it within tight-fitting internal compartments called phagosomes. Another part of the cell called the lysosome then fuses with the phagosome to destroy the bacterium inside.

“We think that this mechanism might also be at play in Parkinson's disease, where abnormal masses of a protein called Lewy bodies build up in neurons in the brain and cause damage,” explained co-lead study investigator Susanne Herbst, Ph.D., a postdoctoral fellow at the Crick Institute.

Using genetic, pharmacological, and proteomics approaches, the investigators found that LRRK2 prevents phagosomes from fusing with lysosomes in both human and mouse macrophages, making them less efficient at clearing bacteria. Deleting the LRRK2 gene or treating the cells with an LRRK2 blocker significantly reduced levels of Mtb. These in vitro findings were supported by experiments in mice. When the researchers deleted the gene for LRRK2 in mice, they found that they exhibited an enhanced early immune response to TB infection and had significantly lower levels of Mtb in their lungs than control mice up to two weeks after infection.

The researchers suspect that LRRK2 might be preventing immune cells in the brain from degrading cell debris properly, leading to a buildup of protein in neurons that disrupts their function.

“By studying TB, we have found a possible explanation for why LRRK2 mutations are a genetic risk factor for Parkinson's disease,” Dr. Herbst It's exciting when different fields of research connect up in unexpected ways like this!”

“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,” added co-lead study investigator Patrick Lewis, Ph.D., associate professor in cellular and molecular neuroscience at the University of Reading. “But over the last few years, there has been a growing appreciation of the integral role of other cells in the brain, and particularly the immune system, in keeping neurons healthy. 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.”

Interestingly, these new findings also suggest that LRRK2 inhibitors could be a powerful new way of combating TB, which kills 1.67 million people every year.

“Drug-resistant TB is a serious emerging problem, and boosting the body's own immune defense against TB is an important step in the battle against antibiotic-resistant strains,” concluded senior study investigator Max Gutierrez, Ph.D., group leader at the Crick Institute. 







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