Protein in Brain Associated with Different Stages of Parkinson’s Disease, Study Shows

An international post-mortem brain study of Parkinson’s disease shows altered levels of the LRRK2 protein are associated with different stages of the disease.

The study, “LRRK2 levels and phosphorylation in Parkinson’s disease brain and cases with restricted Lewy bodies,” was published in the journal Movement Disorders.

Previous studies have shown that mutations in the gene Lrrk2 are a leading cause of familial cases of Parkinson’s. The most common Lrrk2 mutations are known to increase the activity of the protein LRRK2. Drugs blocking LRRK2 protein activity are currently being developed as a potential therapy for the disease.

“We focused on this protein in particular because it holds a lot of promise, and there is currently a bottleneck in known facts about it,” Dr. Nicolas Dzamko from Neuroscience Research Australia (NeuRA) said in a press release.

Both the location and expression levels of LRRK2 in the brains of Parkinson’s patients was still largely unknown. An international group of researchers performed a large study to determine both location and levels of LRRK2 protein using postmortem brain tissue samples from Parkinson’s patients. For controls, they used samples from patients with and without Lewy bodies (abnormal protein aggregates found inside nerve cells).

“This study has given us the most comprehensive picture to date of what is happening with the LRRK2 protein in the brains of people with Parkinson’s disease,” Dzamko said. “There are drugs in development that can act on LRRK2’s activity, but we need to know when to give them to people and which people will most benefit from it.”

Dzamko’s team in Australia collaborated with scientists in California, Amsterdam, London, and Tokyo to map LRRK2 in the brain.

Researchers found that in clinical Parkinson’s disease brain tissue samples, declining LRRK2 levels correlated with increasing disease duration. They also found that a certain modification to LRRK2 protein (specifically, a modification called phosphorylation) was also reduced, suggesting that pathways controlling this protein signaling may also be altered during clinically diagnosed Parkinson’s.

These results support a role for LRRK2 in Parkinson’s in different aspects of the disease and at different stages, and suggest that different therapeutic strategies may be required to treat different stages of the disease.

“We’ve used a large sample size for each area of the brain that we analyzed. Different parts of the brain are affected differently by [Parkinon’s], so we have an even better understanding of where LRRK2 can be found in the brain and at what levels and how these are changed by Parkinson’s disease,” Dzamko said.