Can we predict who is at risk of facing cognitive issues in PD and address them earlier? These are the questions being pursued by Dr. Goldman of the PDF Research Center at Rush University Medical Center.
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William T. Dauer, M.D.
This article originally appeared in the Spring 2008 edition of PDF's quarterly newsletter, News & Review.
It is common for someone recently diagnosed with Parkinson’s to question whether the disease can be passed on to children, grandchildren or other members of the family.
Dr. William Dauer, of Columbia University, notes that most Parkinson’s disease (PD) cases are sporadic — meaning that genetics and family history have not played a clear role in the onset and development of the disease. Of the one million individuals in the US who live with PD, scientists believe that only about five percent have an inherited form of the disease.
Over the past decade, there has been growing recognition of the role that genetic susceptibility plays in the development of PD — meaning that genes may not themselves cause Parkinson’s, but may play a role in making some people more vulnerable to developing the disease than others. Dr. Dauer believes that while the percentage of people who inherit PD is very small, the study of genetic forms of PD can teach us about the more common, non-inherited, forms — and thereby help us develop better therapies to treat it.
In the late 1990s, while working on a PDF-funded Fellowship in Movement Disorders at Columbia University, Dr. Dauer began studying alpha-synuclein, the first protein to be identified (in a mutated form) as a genetic cause of Parkinson’s. Although the cases of genetically-induced PD via alpha-synuclein are rare, the protein is commonly found in substances known as Lewy bodies, which are found in the brains of people with classic PD. This relationship confirms that the study of rare genetic forms of Parkinson’s can lead to insights relevant to sporadic PD.
In 2002, Dr. Dauer developed an important mouse model, in which natural alpha-synuclein had been removed, to examine the link between the genetic and environmental causes of Parkinson’s. His model demonstrated that when an alpha-synuclein-free mouse is exposed to MPTP (a neurotoxin that is widely known to cause PD-like symptoms), the animal does not develop PD symptoms.
The fact that these mice were resistant to MPTP is significant because it showed that a PD-causing gene (mutant alpha-synuclein) affects the role that an environmental toxin plays in causing dopamine loss and PD symptoms. In other words, genes and environmental toxins may act by regulating similar pathways.
Dr. Dauer is now studying LRRK2 (leucine-rich repeat kinase 2), the most common mutated gene to be found among people who have inherited PD. Most people who have PD because of a LRRK2 mutation exhibit symptoms very similar to those found in people with sporadic Parkinson’s. Dr. Dauer reports that the pathologies of LRRK2 PD and sporadic PD are also very similar. This suggests that LRRK2 may also participate in the neuronal pathways that go awry in people with typical PD. Scientists hope that LRRK2 may be a promising drug target as well.
While the links between LRRK2 and alpha-synuclein in classic PD are not yet clear, the work on these and other genes offer hope for understanding the mechanisms underlying classic PD, and for devising new treatment strategies.
William T. Dauer, M.D. is an Assistant Professor of Neurology and Pharmacology at Columbia University Medical Center. His work is supported as part of PDF’s Center Grant to Columbia University amounting to $2.6 million in 2008. Dr. Dauer served on the Scientific Program Committee for PDF’s 50th Anniversary Educational Symposium, where he presented a session entitled, Biology and Pathology of LRRK2.