New Assay for Analyzing Parkinson’s Enzyme Activity Might Aid Drug Development

Researchers have developed a laboratory assay that measures the activity of the mutated LRRK2 gene — the major genetic cause of Parkinson’s disease.

The team behind the study “Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors,” published in the Biochemical Journal, believe that the method could one day be used in screening drugs for activity in inherited Parkinson’s disease caused by a mutation in the LRRK2 gene.

LRRK2 is the most commonly affected gene among patients who have an inherited form of Parkinson’s, but recent research also shows that sporadic Parkinson’s patients often carry mutations in the gene. The team believed that understanding how mutations in the gene can lead to Parkinson’s disease might also lead to drugs targeting the specific molecular problem in these patients.

The most common mutations boost the production of the LRRK2 protein (an enzyme) suggesting that blockers of LRRK2 could slow or treat the disease.

“Current drug treatments only deal with symptoms of the condition, such as tremors, but do not affect the progression of Parkinson’s disease. An important question is whether a LRRK2 therapy might have potential to slow progression of the condition, which no other current therapy is able to do,” Dario Alessi, a professor at the University of Dundee in Scotland and senior author of the study, said in a press release.

Earlier research by the same team has suggested that the LRRK2 enzyme places molecular tags on another protein, called Rab 10, preventing it from working properly. Rab proteins are crucial for numerous cellular functions and studies have shown that patients often have either low numbers or inactive forms of the proteins.

Using Parkinson’s disease mouse models, researchers have now developed an assay measuring how much Rab 10 is deactivated in cells. This is done by the use of the molecular tags placed on Rab by the LRRK2 enzyme, and so, the assay indirectly measures LRRK2 activity.

The new method is simple and straightforward, needing only a small sample of tissue for analysis. It also has the advantage that it is possible to scale up, in case the tool turns out to be valuable in a clinical setting where large numbers of samples are handled. The researchers, however, admit that more research is needed before the tool can help with Parkinson’s drug discovery.

“I am hopeful that the new technology elaborated on in our study will greatly aid future work on defining the role that LRRK2 plays in Parkinson’s disease,” Alessi said.

“If this method can be applied to human samples, it will be a significant step toward earlier and more definitive diagnosis of Parkinson’s, a disease of steadily increasing prevalence that currently affects over 10 million people worldwide,” added Aideen Sullivan, a professor from the University College Cork in Ireland, specializing in Parkinson’s disease.