Parkinson's gene promotes deadly protein over-production

Runaway production of proteins tripped off by a genetic mutation may be the culprit in the neurological damage associated with Parkinson’s disease, the National Institutes of Health announced yesterday.

Two mutations have cropped up in leucine-rich repeat kinase 2 (LRRK2), which could bulk up on the gene’s tagging of ribosomal proteins. Too many of these proteins can lead to nerve cell death.

The study was funded in part by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS). This new understanding could lead to targeted therapies that interrupt the overproduction of proteins within the cell.

“This may be a major discovery for Parkinson’s disease patients,” said Ted Dawson, MD, PhD, director of the Johns Hopkins University Morris K. Udall Center of Excellence for Parkinson’s disease in Baltimore, in the release.

Mutations in the LRRK2 gene have been indicated in up to 10 percent of inherited Parkinson’s and in about 4 percent of those without a history of Parkinson’s in their family. One mutation in particular, G209S, could be at the root of 30 percent to 40 percent of Parkinson’s disease among the North African Arabic demographic. Now that scientists know that LRRK2 is over-tagging the production of protein, the researchers are now trying to find the molecules that LRRK2 tags.

 “For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson’s disease,” added Margaret Sutherland, PhD, a program director at NINDS. “This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson’s disease.”

This research implicates two ribosomal proteins, s11 and s15, which are triggered in excess by LRRK2 mutation, and brain tissue samples showed higher levels of phosphorylated s15 than in healthy controls. This system of phosphorylation was linked with cell death in further studies. By blocking this mechanism in studies with fruit flies, the scientists were able to restore movement and prevent further nerve cell damage.

“These results suggest that s15 ribosome protein may play a critical role in the development of Parkinson’s disease,” said Dawson. Measurements of s15 phosphorylation could one day be a biomarker for LRRK2 activity in LRRK2-inhibitor drug trials.