A mutation in the leucine rich repeat kinase 2 (LRRK2) gene — the most common cause of inherited Parkinson’s disease — alters cells circulating outside the brain, not within, offering a new understanding of what causes the disease.
The most common Parkinson’s gene mutation may change how immune cells react to generic infections like colds, which in turn trigger the inflammatory reaction in the brain that causes Parkinson’s disease. Image credit: Blausen Gallery 2014 / Wikiversity Journal of Medicine, doi: 10.15347/wjm/2014.010.
“We know that brain cells called microglia cause the inflammation that ultimately destroys the area of the brain responsible for movement in Parkinson’s,” said Dr. Richard Smeyne, Director of the Jefferson Comprehensive Parkinson’s Disease and Movement Disorder Center at the Vickie and Jack Farber Institute for Neuroscience.
“But it wasn’t clear how a common inherited mutation was involved in that process, and whether the mutation altered microglia.”
Dr. Smeyne and co-authors looked at the mutant version of the LRRK2 (pronounced ‘lark’) gene.
“We know that gene mutation is not enough to cause the disease. We know that twins who both carry the mutation, won’t both necessarily develop Parkinson’s. A second ‘hit’ or initiating event is needed,” said Dr. Elena Kozina, a postdoctoral researcher at Philadelphia University and Thomas Jefferson University.
Based on the earlier work showing that the flu might increase risk of Parkinson’s disease, the team decided to investigate whether that second hit came from an infection.
Suspecting that the LRRK2 mutations might be acting outside of the brain, the researchers used an agent — the outer shell of bacteria, called lipopolysaccharide (LPS) — that causes an immune reaction.
LPS itself does not pass into the brain, nor do the immune cells it activates, which made it ideal for testing whether this second hit was acting directly in the brain.
When the study authors gave the bacterial fragments to the mice carrying the two most common LRRK2 gene mutations, the immune reaction became a ‘cytokine storm,’ with inflammatory mediators rising to levels that 3-5 times higher than a normal reaction to LPS.
These inflammatory mediators were produced by T and B immune cells expressing the LRRK2 mutation.
Despite the fact that LPS did not cross the blood-brain barrier, the scientists showed that the elevated cytokines were able to enter the brain, creating an environment that caused the microglia to activate pathologically and destroy the brain region involved in movement.
“Although more tests are needed to prove the link, as well as testing whether the same is true in humans, these findings give us a new way to think about how these mutations could cause Parkinson’s,” Dr. Smeyne said.
“Although we can’t treat people with immunosuppressants their whole lives to prevent the disease, if this mechanism is confirmed, it’s possible that other interventions could be effective at reducing the chance of developing the disease.”
The findings appear online this week in the journal Brain.
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Elena Kozina et al. Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo. Brain, published online March 21, 2018; doi: 10.1093/brain/awy077
