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| The Parkinson's gene LRRK2 can kill nerve cells (green) by tagging the s15 ribosomal protein (purple).--Courtesy of Dawson lab, Johns Hopkins University Morris K. Udall Center of Excellence for Parkinson's Disease |
Researchers may have discovered how a genetic mechanism in a common cause of Parkinson's works to destroy brain cells in patients--a finding that could help scientists develop new therapies for the devastating disease.
Though most causes of Parkinson's cases are unknown, mutations in a gene called leucine-rich repeat kinase 2--or LRRK2, pronounced "lark two" or "lurk two"--have been implicated in as many as 10% of inherited forms of the disease and in about 4% of patients who have no family history. How exactly these mutations may lead to Parkinson's has not been understood.
But a team of scientists may have solved that mystery. The NIH-supported team found that these mutations may increase the rate at which LRRK2, a kinase enzyme, tags molecules with chemicals called phosphate groups. Specifically, scientists found that these mutations speed up the rate at which it tags two ribosomal proteins, called s11 and s15--key components of proteinmaking machinery inside cells.
This process could cause the cellular machinery to produce too many proteins, inducing cell death. When scientists analyzed brain tissue samples from patients with LRRK2 mutations, they found higher levels of phosphorylated s15 than in control subjects. The phosphorylation process helps regulate basic nerve cell function and health.
"For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson's disease," said Margaret Sutherland, a program director at NIH's National Institute of Neurological Disorders and Stroke. "This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson's disease."
To test this link, scientists genetically engineered cells derived from rats and from human embryonic stem cells to have a LRRK2 mutant gene. In both instances, this increased the rate of cell death and phosphorylated s15.
In flies with dopamine-releasing nerve cells genetically altered to overproduce LRRK2, scientists found heightened levels of phosphorylated s15. By engineering the flies so that s15 could not be tagged by LRRK2, the investigators prevented cell damage and restored normal movement.
The results are published in the journal Cell.
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- see the study abstract