Too much protein (in excess) may kill brain cells as Parkinson's disease progresses
Too much protein (in excess) may kill brain cells as Parkinson's disease progresses
Posted on Thursday, April 10, 2014
An NIH-funded trial on key genes in Parkinson's disease has identified a possible new target for controlling the disease.
Researchers have apparently succeeded in identifying how the main genetic cause of Parkinson's disease destroys brain cells and affects many patients worldwide. The research was funded in part by the US National Institutes of Health (NIH) and the National Institute of Neurological Disorders and Stroke, and its results may help scientists develop new treatments.
Parkinson's killers lurk as seen in NIH-funded research where the lethal LRRK2 gene can kill nerve cells (green) by tagging the S15 ribosomal proteins (purple), a cog in the cell's protein production system. Courtesy of DAWSON LABORATORY JHU MORRIS K. UDALL PARKINSON'S DISEASE CENTER OF EXCELLENCE.
"This may be a significant discovery for Parkinson's patients," says Dr. Ted Dawson, director of the JHU Morris K. UDALL Center for Parkinson's Disease Excellence at Johns Hopkins University in Baltimore. Dr. Dawson and his wife Dr. Velina Dawson, Director of the JHU Stem Cell and Neurodegeneration Program in the Cell Engineering Institute led the research, the results of which were published in CELL.
The researchers found that mutations in the gene called LEUCINE - RICH REPEATE KINASE 2 (LRRK2 also known as Lurk 2) can increase the rate at which LRRK2 ribosomal proteins, which are an important step in the creation of intracellular proteins, are created. This can stimulate the creation of excess proteins and this leads to cell death.
"For about a decade, scientists have tried to find how mutations in the LRRK2 gene cause Parkinson's disease," says Dr. Margaret Sutherland, director of the program at NINDS. "This study shows a clear link between LRRK2 and a pathogenic mechanism associated with Parkinson's disease."
Parkinson's disease affects more than half a million people in the United States and is a degenerative disease that attacks nerve cells in many areas of the nervous system and mainly in an area of the brain called SUBSTANIA NIGRA (black matter), which releases dopamine, an important chemical messenger for movement. Initially, Parkinson's disease causes uncontrolled movements, including tremors in the hands, arms and legs As the disease progresses, patients lose the ability to walk, talk, or perform simple tasks.
In most cases the cause of the disease is unknown. Mutations in the LRRK2 gene are the main genetic causes. About 10% of the hereditary forms of the disease and about 4% of patients who have no family background were attributed to them. One study showed that the most common mutation in the LRRK2 gene, called G2019S, may be the cause of 30-40% of all Parkinson's cases in descendants of Shah Arabs from North Africa.
The enzyme created from the LRRK2 gene is a kinase-type enzyme, an intracellular protein that attaches phosphoric groups to molecules. The process of phosphorylation helps to regulate basic functions of nerve cells and their health. Earlier studies showed that disease-causing mutations such as G2019S increase the rate of phosphorylation. Identifying the molecules that are phosphorylated by the LRRK2 gene could hint at how nerve cells die in Parkinson's disease.
In the current study, the researchers used the LRRK2 gene as bait to fish out the proteins that it phosphorylates under normal conditions. Many studies conducted in human kidney cells have shown that the LRRK2 gene phosphorylates ribosomal proteins. These together with other molecules - nucleic acids form the ribosomes that are used as the factories of the cell to produce proteins.
Additional studies have shown that disease-causing mutations in the LRRK2 gene increase the rate of phosphorylation of two ribosomal proteins called S11 and S15. In addition, high levels of phosphorylated S2 protein were seen in the brain tissue samples of patients with mutations in the LRRK15 gene compared to a control group.
In the next step, the researchers checked whether it is possible to link between phosphorylation and cell death by examining a rat nerve or from a source of human stem cells. In cells genetically engineered to contain the mutations of the LRRK2 gene, greater mortality and a greater amount of phosphorylated protein S15 were observed. In contrast, the researchers prevented cell death by engineering the same cells to create a non-phosphorylatable S15 protein.
"These results show that the ribosomal protein S15 plays a key role in the development of Parkinson's disease," says Dr. Dawson.
How can phosphorylation of the S15 protein cause neuronal cell death? To test this, Dr. Dawson and his team conducted studies on fruit flies.
Previous studies in flies showed that dopamine-secreting cells engineered to produce excess LRRK2 gene products produced nerve cell damage along with movement disorders. The researchers found that the flies' brains contained high levels of the phosphorylated S15 protein. And after they were engineered so that the S15 protein would not be phosphorylated by the LRRK2 gene, the damage to the cells was prevented, as were the movement disorders.
Interestingly, the brains of the flies with mutations in the LRRK2 gene contained high and abnormal levels of all proteins, indicating that an increase in the level of the phosphorylated protein caused an increased production of ribosomal protein. Treatment of flies with a low level of ANISOMYCIN, a drug that blocks protein production, prevented nerve damage and restored motility to a normal state, despite high levels of the S15 phosphorylated protein.
"Our results support the idea that changes in the way cells produce protein can be a common cause of the development of Parkinson's disease and probably also other neurodegenerative diseases of the nervous system," says Dr. Dawson.
Dr. Dawson and his team think that blocking the phosphorylation of the ribosomal protein S15 can lead to the development of a drug as well as other approaches in which the creation of the protein in the cells will be reduced or their ability to deal with high protein levels will be improved. In addition, they think that means of measuring levels of phosphorylated S15 could make it a biomarker for the activity of the LRRK2 gene in treatment trials of its inhibitors.
This study was supported by research grants from NINDS (NS038377, NS072187), the JBP Foundation, the Maryland Foundation for Stem Cell Research (2007MSCRFI-0420-00 and 2009-MSCRFI-0125-00 and 2013-MSCRFII-0195-00) and the New Stem Cell Foundation. York
For more information on Parkinson's disease please visit the following website:
http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm
NINDS is the primary funder of brain and nervous system research. His mission is to obtain basic information about the brain and nervous system and use this information to reduce suffering from nervous system diseases.
NIH is the main government medical research body in the USA. It includes 27 institutes and centers and is located in the US Department of Health. The NIH is basically a federal agency that performs and supports basic, clinical and international medical research and investigates the causes and treatments of common and rare diseases. For more information
NIH turns discoveries into health.
bibliography
Martin et al. "Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease," Cell, April 10, 2014. DOI: 10.1016/j.cell.2014.01.064
