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April 28, 2014
Insights into Mutations That Cause Parkinson’s Disease
Researchers determined how an abnormal gene begins the process that leads to neuron death and Parkinson’s disease. The finding hints at potential new therapies for the movement disorder.
Parkinson’s disease is a degenerative disorder that destroys neurons in the brain. The loss of neurons leads to movement difficulties that include trembling of the hands, arms, legs, jaw, or head; slowed movements; muscle stiffness; and impaired balance. Medications or surgery can often improve symptoms, but currently there’s no cure.
While the exact causes of Parkinson’s disease aren’t known, scientists have identified several genes that are linked to the disorder. Misspellings in one gene, LRRK2 are the most common genetic cause of the disease. LRRK2 mutations have been implicated in about 10% of inherited forms of Parkinson’s and in about 4% of patients with no family history of the disease. The most common LRRK2 mutation, called G2019S, is thought to be the cause of 30-40% of Parkinson’s cases in people of North African Arabic descent.
A team led by Drs. Ted Dawson and Valina Dawson at the Johns Hopkins University set out to learn why mutations in the LRRK2 gene might lead to Parkinson’s disease. Their study was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results appeared online on April 10, 2014, in Cell.
LRRK2 is an enzyme that attaches chemical tags, known as phosphate groups, to proteins. To determine exactly what proteins are tagged by LRRK2, the team used it as bait to fish out the proteins. They discovered that LRRK2 attaches phosphate groups to many ribosomal proteins, including one called s15. Ribosomes are the complex molecular machines that manufacture proteins for the cell.
The group found that rat and human neurons with a mutated form of LRRK2 had increased tagging of the ribosomal protein s15, and more of these nerve cells died. When s15 was altered so it couldn’t be tagged by LRRK2, less cell death occurred, demonstrating a connection between the tagging and cell death. The group also found that 4 brain tissue samples from patients with LRRK2 mutations had greater levels of phosphorylated s15 than healthy controls.
To better understand the molecular mechanisms at work, the team turned to a fruit fly model of Parkinson’s disease. They found that the brains of flies expressing mutant human LRRK2 had abnormally high protein levels, showing that increased s15 tagging caused ribosomes to make too much protein. Treating flies with a drug that blocked protein production prevented nerve cell damage and restored the flies’ movement—even though levels of s15 phosphorylation remained high. Altered s15 that couldn’t be tagged by LRRK2 prevented cell damage and restored normal movement to flies.
These findings suggest that misspellings in the LRRK2 gene may lead to Parkinson’s disease by abnormally increasing protein synthesis in neurons.
“This may be a major discovery for Parkinson’s disease patients,” Ted Dawson says. “Our results support the idea that changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders.” The team next plans to determine how excess protein production might cause neurons to degenerate.
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Reference: Ribosomal Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson's Disease. Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL. Cell. 2014 Apr 10;157(2):472-85. doi: 10.1016/j.cell.2014.01.064. PMID: 24725412.
Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS); JPB Foundation; Maryland Stem Cell Research Fund; New York Stem Cell Foundation; Adrienne Helis Malvin Medical Research Foundation; Diana Helis Henry Medical Research Foundation; and Merck KGAA.