How does the most common genetic cause of Parkinson’s Disease (LRRK2) cause Parkinson’s disease and could it help us develop a better therapy?
You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life.
Currently, approximately 10% of Parkinson’s disease cases have been associated with gene defects. These changes in the DNA have allowed researchers to hone in on the mechanisms that may be responsible for this devastating disease. Scientists around the world have become adept at preparing animal models of Parkinson’s disease by using the observed changes in the DNA occurring in some human cases. Ted and Valina Dawson, a husband and wife team located at the National Parkinson Foundation Center of Excellence at Johns Hopkins in Baltimore, MD recently published an important paper on how the most common genetic subtype of Parkinson’s disease (LRRK2) leads to degeneration and to cell death. In this month’s What’s Hot in PD? Column I will discuss the findings from this exciting paper, and also cover the possible implications for the field.
Mutations in the DNA of Parkinson’s disease patients located in the leucine-rich repeat kinase 2 region (LRRK2) represent the most common genetic cause of Parkinson's disease. Because LRRK2 is the most common gene defect responsible for Parkinson’s disease, it has been a focus of many laboratories. So what does LRRK2 do? One of the jobs of LRRK2 in the brain seems to be to tag proteins. When proteins are tagged, this signals the brain to change its cell manufacturing process. However, when bad LRRK2 tags proteins, it results in over-manufacturing. An excess of proteins can lead to the death of brain cells. Bad LRRK2 performs its tagging function by attaching what have been referred to as phosphate groups. Bad LRRK2 leads to increases in proteins through its action on a part of the cell called ribosomal s15. The Dawsons demonstrated that removing the phosphate group tagging of s15 prevented degeneration. Further, by administering a low dose of anisomycin, which blocks protein production, the Dawson strategy also rescued flies with LRRK2 mutations.
Though these findings are exciting, we should remember that they have yet to be translated into humans. The Dawsons suggest that one way to treat LRRK2 Parkinson’s disease would be to simply block phosphorylation of the s15 ribosomal protein. This idea may be formulated into a strategy for a future human clinical drug trial. Further, if there is a clinical trial, we will need a way to measure success and to monitor s15 phosphorylation. Phosphorylation could possibly be a blood or other biomarker of bad LRRK2 activity. Though there are many steps remaining in human translation, the findings from this recent paper provide something for the Parkinson’s community to cheer about.
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. Ribosomal Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson's Disease. Cell. 2014 Apr 10;157(2):472-85. doi:10.1016/j.cell.2014.01.064. PubMed PMID: 24725412.
Posted: 5/1/2014 6:00:00 AM by
Browse current and archived What's Hot in PD? articles, the National Parkinson Foundation's monthly blog for people with Parkinson's written by our National Medical Director, Dr. Michael S. Okun.
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