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Bringing Genetics to the Clinic
Among the most exciting advances in Parkinson’s disease (PD) research in the last decade has been the discovery of several genes that are linked to the disease. Yet very few diagnoses of Parkinson’s — perhaps only five percent — can be attributed wholly to faulty genes (see the article by Dr. Matthew Farrer).
The research of PDF-funded investigator Christine Klein, M.D., has helped to translate the fruits of genetic discoveries in the lab to benefit people with Parkinson’s disease in the clinic. She received the first of her two PDF International Research Grants in 2001 (the other came in 2003), at a time when she was just establishing herself as an independent researcher. The PDF grants enable scientists at the early stages of their careers to test original ideas and build the preliminary data that are required for larger grants from major funding sources.
Dr. Klein became interested in Parkinson’s genetics in the late 1990s, just as the field was opening up. While working as a postdoctoral fellow in a group led by Xandra Breakefield, Ph.D., at Harvard Medical School, she learned of a family in which many members had a form of Parkinson’s and found out that it was caused by a newly discovered gene called Parkin. It was the second Parkinson’s-related gene to be discovered. (The first, alpha-synuclein, was reported in 1997 by a team led by Roger Duvoisin, M.D., the first postdoctoral fellow supported by PDF in 1962.)
At the time Dr. Klein began her PDF-funded work on this family, certain mutations in Parkin had already been linked to Parkinson’s. Such mutations are a kind of “spelling error” — that is, changes in the sequence of letters that stand for a gene’s molecular components.
Dr. Klein found an entirely different set of mutations: deletions and duplications of entire sections of the gene. It turns out that such deletions and duplications make up about 80 percent of all Parkin mutations.
Dr. Klein’s discoveries did not end there; she helped to develop the first "assay," or small-scale genetic test, that would identify people who have Parkin mutations. She published these discoveries in 2001. Her findings led to accurate and sensitive genetic tests for the gene.
Today, Dr. Klein is a professor at the University of Lübeck, Germany, and is building upon these earlier discoveries (being able to identify people whose Parkinson’s is caused by Parkin), to study the brain changes in Parkinson’s and to improve care for her patients.
In one approach, she uses imaging techniques such as MRI and PET scans to compare the brains of people with Parkinson’s caused by Parkin with those of people who carry Parkin mutations but have not yet developed symptoms of Parkinson’s. The hope is to identify brain changes that occur early in the disease, before motor symptoms develop. This would allow for early diagnosis and also shed light on how the brains of people with Parkinson’s are altered by the disease.
As a clinician, Dr. Klein is always concerned with what her genetics research means for her patients. “Recently I have seen three young women with a diagnosis of Parkin mutations,” says Dr. Klein. “They wanted answers. Knowing that they had these mutations, they could put a name to the disease, and I could counsel them that this form of Parkinson’s disease responds well to medications and rarely leads to dementia.”
With these projects and others, she says, “I’m trying to bridge the gap between clinical findings and research, and then back again.”
Dr. Klein is head of the Research Group on Clinical and Molecular Neurogenetics at the University of Lübeck in Germany. Her work was funded through the International Research Grants Program. In FY2012, PDF is supporting the program with $825,000.