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Laboratory of Neurogenetics
Movement Disorders
Many movement disorders are familial and have an underlying genetic basis. Movement disorders can be studied using recent advances in molecular genetics. Finding the genes involved will give us clues about the actual causes of these disorders and will help us understand the forms of movement disorders that aren't inherited. (termed sporadic disease)
What is DNA and what does Genetics have to do with Parkinson's Disease (PD)?
Deoxyribonucleic acid (DNA) encodes the biological blueprint of life in all its diversity. The chemical is composed of four types of nucleotides or bases, A, C, G and T...e.g. GGCGAAACTATCACT. The sequence encodes thousands of proteins that make up the cells, tissues, and organs of every living organism.
Less than a decade ago, it was believed that many movement disorders, including Parkinson's disease could not be genetic. Since that time, many genetic locations (loci) have been found to be associated with various movement disorders.
Lewy Bodies and PD, how does our research play a role?
Lewy Bodies-microscopic deposits, or lesions, of abnormally aggregated proteins found within nerve cells.Lewy bodies are microscopic deposits, or lesions, of abnormally aggregated proteins found within nerve cells. In most cases of Parkinson's disease, Lewy bodies can be found in the brainstem, including the substantia nigra. More recent studies have suggested that a few Lewy bodies can also be deposited in other brain regions, including the cortex. And finally, a few Lewy bodies may also be found in the brains of elderly people without disease.

Our knowledge of what Lewy bodies are, how they form and why they are associated with Parkinson's disease is sparse. Insight can be gained by looking at other diseases with these deposits. In diffuse Lewy body disease (DLBD), a condition far more rare than Parkinson's disease, Lewy bodies are far more numerous and widespread. Memory loss may be a problem. It is currently debated whether DLBD could represent an extremely severe form of Parkinson's disease.
In the brain stem, at very high magnification, Lewy bodies appear to have a dense, granular center surrounded by concentric rings of radiating neurofilament protein. Other constituents include ubiquitin and ubiquitin C-terminal hydrolase. However, most recently, by genetic studies on a family from Italy (the Contursi kindred), a new component, alpha-synuclein, was discovered. A mutation in the alpha-synuclein gene leads to early-onset Lewy body parkinsonism in this family. However, in ordinary Parkinson's disease, alpha-synuclein is also present in dramatic amounts in Lewy bodies. We hope that more genetic studies, with the help of other families with Parkinson's disease, will allow us to identify more components. Finding the other pieces in the puzzle will allow us to discover what Lewy bodies are made of and why they form. This knowledge will enable us to make breakthroughs in future treatments for Parkinson's disease.
Much is published about Dopamine and Parkinson's disease. Why aren't you studying Dopamine instead of Genetics?
Dopamine is the neurotransmitter lost in Parkinson's disease. The main pharmacological (medication) therapies to treat the disorder are based on dopamine replacement, either directly (through levodopa, in the form of SinemetTM) or indirectly by medications which resemble dopamine (dopamine agonists). Dopamine does not pass into the brain from the stomach (does not cross the blood-brain barrier) and is quickly degraded in the blood stream. However, levodopa, a related brain chemical, can cross into the brain from the bloodstream. The brain is able to make dopamine from levodopa. Another way that the level of dopamine can be maintained in the nervous system is to try and prevent its natural breakdown in the body. Major enzymes which metabolize and degrade dopamine are monoamine oxidase (MAO, types A and B) and c-o-methyl transferase (COMT). Medications which inhibit these reactions are selegeline (EldeprylTM) which inhibits MAO-B and tolcapone (TasmarTM) which inhibits COMT. Although all these medications are helpful in treating some of the symptoms of Parkinson's disease, they do not address the cause, the loss of dopaminergic neurons. Why this occurs remains unknown.
Why isn't replacing the lost brain dopamine a cure for Parkinson's disease?
The answer to this is complicated. However, essentially, other areas in the brain and other neurotransmitters are affected. Abnormal, microscopic, neurofilament-filled deposits, called Lewy bodies may be found in the affected neurons. In Parkinson's disease, Lewy bodies are found in the surviving cells of the substantia nigra, but also, in other brain structures especially later in the illness. Lewy bodies are the hallmark of a group of related disorders with parkinsonism, termed diffuse Lewy body disease (DLBD) where these deposits are more widespread throughout the brain.
Giving dopamine replacement is a good strategy, but it does not prevent the underlying cause of the Parkinson's or DLBD. We want to find out more about Lewy bodies, what they are, how and why are they formed and what we can do to prevent their formation? One of the best ways to do this is to study familial Lewy body diseases, including, familial Parkinson's disease, a very important subset of Lewy body disease.
Are most cases of PD genetic? If not, then why is studying the genetics of PD important?
Most cases of PD are not genetic, although genetic risk may play a role. The families which we study, in which there is a large genetic component, are rare. However, studying them is very important. By isolating the gene responsible for PD in those families, we can learn about the biology of the disease in other families and in sporadic cases of PD ("idiopathic PD"). Once a gene is identified, its function can be studied. This is done on the level of biochemistry, in cells grown in culture in the lab, and by using the DNA sequence information. Also, we develop mice which carry the "PD causing" mutation. We study the behavior, movement, and the brains of these mice to see what is abnormal in them. We can also develop treatments using these mice, which could later be used in humans. A similar strategy is currently well under way in the area of Alzheimer's disease, and has been leading to some major breakthroughs using genes discovered in our laboratories.
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Updated: Wednesday July 28, 2010