Mutation Can Trigger Parkinson’s Outside the Brain, Study Finds

José Lopes, PhD avatar

by José Lopes, PhD |

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Parkinson's and IL-17A

The most common gene mutation in Parkinson’s triggers disease outside the brain by changing the body’s immune response to common infections, a study in mice reports.

The research, “Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo,” was published in the journal Brain.

Parkinson’s patients typically lose dopamine nerve cells in a brain area called substantia nigra, resulting in protein clumps known as Lewy bodies and an increase in brain inflammatory cells. In fact, increasing evidence shows that nerve cell inflammation is key to the development of the disease.

“We know that brain cells called microglia cause the inflammation that ultimately destroys the area of the brain responsible for movement in Parkinson’s,” Dr. Richard J. Smeyne, the study’s senior author, said in a press release. “But it wasn’t clear how a common inherited mutation was involved in that process, and whether the mutation altered microglia.”

Only 10 percent of Parkinson’s cases have a genetic cause. Among these, LRRK2 gene cause the most cases. Mutated LRRK2 is found in 15 to 20 percent of Parkinson’s patients who are Ashkenazi Jews patients and in 40 percent of patients who are North African Arab Berbers.

But the precise link between LRRK2 and Parkinson’s remains poorly understood.

“We know that gene mutation is not enough to cause the disease,” said Dr. Elena Kozina, the study’s first author. “We know that twins who both carry the mutation won’t both necessarily develop Parkinson’s.” Another “initiating event,” or hit, is needed, she said.

Smeyne’s team had already observed that a certain strain of influenza virus predisposed mice to develop disease characteristics that mimic Parkinson’s. This prompted them to wonder if a second hit could come from an infection.

The scientists suspected that LRRK2 mutations could be causing effects outside the brain. To test that idea, they used lipopolysaccharide (LPS) — the major component of the outer shell of gram-negative bacteria — to trigger an immune reaction in the mice.

Neither LPS nor the immune cells it activates are able to cross the blood-brain barrier. This gave the team the perfect tool to test whether inflammation on the periphery affects the brain.

They gave LPS to mice with high levels of the two most common LRRK2 gene mutations. LPS triggered a three to five-fold increase in inflammatory regulators, called cytokines, in these mice, compared with control mice and mice with normal LRRK2.

The cytokines were produced by immune T- and B-cells, two types of white blood cells.

Mice with high levels of cytokines also showed enhanced LRRK2 gene expression in certain immune cells and in activated cells of the brain. This led to nerve cell loss in the substantia nigra, a brain area that plays a critical role in movement.

Nerve cell inflammation in these mice may have been triggered by the ability of circulating cytokines to cross the blood-brain barrier and enter the brain, the team said. This could have created an environment that led to the destruction of the substantia nigra and therefore, movement impairment.

”Overall, this study suggests that peripheral immune signaling plays an unexpected — but important — role in the regulation of neurodegeneration in LRRK2-associated Parkinson’s disease, and provides new targets for interfering with the onset and progression of the disease,” the researchers wrote.

Smeyne cautioned that further research is needed to confirm this link and test it in humans. However, “these findings give us a new way to think about how these mutations could cause Parkinson’s,” he 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,” Smeyne added.

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