The mechanism used by the immune system for clearance of bacterial infections like tuberculosis (TB) might also be implicated in Parkinson’s disease, according to a new study published in The EMBO Journal. This collaborative study provides a possible explanation of the cause of Parkinson’s disease and suggests that drugs designed for Parkinson’s treatment might work for TB too.
The study was conducted by Anetta Härtlova, MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK, and colleagues to determine the potential cause of Parkinson’s disease for improvement n its treatment.
The biological causes of Parkinson’s remain largely unknown, making it more difficult to develop and improve treatments. Discovering a mechanism that causes Parkinson’s and how drugs affect it could significantly advance efforts to improve treatments.
The most common genetic mutation in Parkinson’s disease patients is in a gene called leucine‐rich repeat kinase 2 (LRRK2), which makes the LRRK2 protein overactive. Possible immune functions of LRRK2 have remained ill‐defined. Genetic, pharmacological and proteomics approaches now reveal it as a negative regulator of phagosome maturation in macrophages, thereby affecting the control of Mycobacterium tuberculosis (Mtb) infection. Thus, the 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.
By studying what LRRK2 does in immune cells called macrophages that are infected with Mycobacterium tuberculosis (Mtb) – the bacterium that causes TB – researchers believe 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.
Based on the study, the researchers found that 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 findings in cells 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.
“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.
The team suspects that LRRK2 might be preventing immune cells in the brain from degrading cell debris properly, leading to a build-up of protein in neurons that disrupts their function.
Susanne added: “By studying TB, we have found a possible explanation for why LRRK2 mutations are a genetic risk factor for Parkinson’s disease. It’s exciting when different fields of research connect up in unexpected ways like this!”
Co-author Patrick Lewis, Associate Professor in Cellular and Molecular Neuroscience at the University of Reading, said: “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. 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.”
The results indicate that LRRK2 and its kinase activity affect not only Mtb replication in both human and mouse macrophages by regulating phagosome maturation but also cytokine responses.
For further information click on the link: http://dx.doi.org/10.15252/embj.201798694