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Parkinson’s disease (PD) Newsletter: Our Neurogenetics group at the National Institutes of Health in Bethesda, MD works on neurodegenerative disorders. Our Laboratory lead by Dr. John Hardy, Laboratory Chief at the National Institute on Aging (NIA) is comprised of several parts: Molecular Genetics (led by Dr. Andrew Singleton), Cell Biology (led by Dr. Mark Cookson), and Bioinformatics (led by Dr. Jamie Duckworth). Our group also includes a clinical team. The clinical team is spearheaded by investigators from the National Institute on Neurological Disorders and Stroke (NINDS) (including Drs. Ravina and Gwinn-Hardy) and includes others from the National Human Genome Institute (NHGRI, Dr. Nussbaum) and the NIA (Dr. Salerno). We also have collaborators inside the NIH and outside at other institutions. Since 1986, our lab has had a very simple philosophy: find the genes and gene mutations that cause or contribute to neurological disease. So how do we do this? A successful approach that we’ve used in the past is to find families in which a disease is more common than you would expect by chance. Take the family below for example; in this family there are a set of grandparents with four children. Two of these children also have children (2 girls with PD in one instance, 2 boys and 1 girl in the other). Let us say the people shaded in red have PD the ones in yellow have no symptoms. The incidence of PD in the general population is thought to be so the number of PD cases observed in this family is well in excess of what you would normally expect. When a situation like this occurs it generally means one of two things; there is a shared environmental factor that is causing the disease or there is a genetic predisposition to disease. The occurrence of PD in multiple generations in this family makes the second option the more likely. The genome is comprised 22 pairs of chromosomes and 2 X chromosomes (female) or an X and a Y chromosome (male). Every cell in the body contains a copy of the genome. We inherit one of each pair of chromosomes from our father and the other from our mother. In turn we then pass on a mixture of our fathers and mothers chromosomes to our children. Within these chromosomes are around 35,000 genes which contain the instructions on how to produce proteins. Most often diseases such as the inherited PD seen in this pedigree are caused by a single change in a single gene. Currently it is impossible to look at all 35,000 genes at once, so, in order to find this change we have to narrow down the number of genes we need to examine. To do this we use a technique called linkage. Basically we examine small regions of the genome and follow the inheritance of that section through a family. Lets look at the family again, with additional genetic information. Imagine the colored bars represent a small section of the genome (let’s say about 1/1000th). Again it’s important to remember that each section of the genome comes as a pair, half inherited from your father and half from your mother. Using “markers” we can distinguish between the two halves of these pairs and trace their inheritance through a family. This allows us to find a section of the genome that is always inherited with disease. Geneticists call this segregation and you can see that in this family the bright green section of the genome is always inherited with disease. This tells us that the gene defect is somewhere around this region of the genome. The larger the family is the more confident we can be of this result. Usually this stage will allow us to narrow down the number of genes we are interested in to 300 or so. We then systematically examine each gene for a change (called a mutation) that is likely to cause disease. Technological advances over the last 10 years has meant that the whole process from finding families to finding mutations is a lot quicker, however this approach still generally takes 5 to 15 years of research! So given the incredible amount of time and effort needed to find these mutations why do we do it? These discoveries allow us and others to transfer those genes and mutations into cells and mice in order to make a model which helps the field to better understand disease processes. As more is understood about the disease progression we can then use these models to test therapies. It is only by appreciating how a disease begins and progresses that scientists can make informed attempts at halting or reversing disease progression. We have been a key laboratory in furthering the basic understanding of Alzheimer’s disease progression and are now applying these techniques to a host of other diseases, including PD, Stroke, Dystonia, and Restless Legs Syndrome to name a few. As part of our research, we collect families and individuals with movement disorders, which includes PD. Our research focuses on family collection and using genetics as a tool to find new genes. Because genes are most easily discovered in large families, we are very interested in learning about individuals with PD who have a family history of this disorder. Finding new genes or expanding the knowledge of genes previously described for PD will help to decipher the biological pathways involved in disease development. We would like to follow up on previous research performed by our laboratory and other research laboratories on PD. In order to do this, we need participation from families with a history of PD and participation from individuals with no family history of PD. For families with a history of PD, it is important that both affected and unaffected family members participate. If you are interested in participating in our research on PD or have study related questions, please contact our clinical coordinator listed below by email or telephone. For more information about our research group or our location: http://www.grc.nia.nih.gov/branches/lng/lng.htm. Amanda Singleton NIH/NINDS Bldg. 10/ 6C103A 9000 Rockville Pike Bethesda, MD 20850 [log in to unmask] 301-402-6231 301-480-0335 fax ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn