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Associate Professor of Medicinal & Natural Products Chemistry
Office: S328 PHARIowa City, IA 52242
Email: firstname.lastname@example.orgWeb: More About Dr. Doorn - Related Websites and Resources
BS, Biochemistry, Calvin CollegeMS, Toxicology, University of Michigan-Ann ArborPhD, Toxicology, University of Michigan-Ann Arbor
Interdisciplinary Graduate Program in Human Toxicology
"Parkinson's disease (PD) is a debilitating pathological condition, involving selective degeneration of dopaminergic cells in the nervous system. Symptoms include tremors, impaired motor control and even depression. It is the second most common neurodegenerative disease, affecting approximately one million individuals in the United States. At this point, the cause of the disease is not known and there is no cure. Genetics may play a role in disease pathogenesis, but the vast majority of cases are of unknown origin and may stem from exposure to environmental agents (1).
Research in the Doorn Group centers around a reactive intermediate of dopamine (DA) metabolism. The ultimate goal of this work is to determine whether protein modification by this reactive intermediate plays a role in neurodegenerative disease, particularly, Parkinson's disease.
As shown below, DA undergoes metabolism to an aldehyde intermediate, named 3, 4-dihydroxyphenylacetaldehyde (DOPAL). The primary pathway for biotransformation of DOPAL is via mitochondrial aldehyde dehydrogenase (ALDH2), requiring the cofactor NAD. Past (2) as well as recent (3, 4) studies have demonstrated that DOPAL is reactive toward proteins (see below) and toxic to dopaminergic cells. Therefore, if the metabolism of DOPAL were impaired, the aldehyde may accumulate in the cell to aberrant levels. Does such a mechanism explain the selective toxicity (i.e. dopaminergic cell death) observed in PD? How is DOPAL metabolism impaired? Can environmental agents inhibit DOPAL biotransformation? What is the mechanism of DOPAL-mediated toxicity? These are some questions we hope to answer.
Current (exciting) research in the Doorn Group includes:
1. Developing novel means to produce DOPAL in significant quantities for biochemical and biological studies.
In the past, a biosynthetic pathway was utilized (5, 6), involving rat liver monoamine oxidase to convert DA to DOPAL. We improved the yields from 5-30% to 70-80% via a simple modification. However, a new/novel synthetic scheme (below) was developed to obtain sufficient amounts for further chemical, biochemical and biological studies. This synthetic method utilizes inexpensive, commercially available material, and is quick and easy.
2. Elucidating mechanisms for generation of DOPAL at aberrant levels. Recently acquired data demonstrate that a product of oxidative stress potently inhibits ALDH2-mediated oxidation of DOPAL. Work in progress is examining the role of environmental and pharmacological agents.
3. Identifying proteins modified by DOPAL. We are developing a proteomics-based approach to identify proteins modified by DOPAL. Other novel methods (i.e. besides antibodies) are being developed to assist with this. Current work is focusing on the mitochondria, as this is the site of DOPAL production.
4. Determine functional consequence of protein modification by DOPAL. Does modification of a protein by DOPAL impair function?
5. Development of novel means for therapeutic intervention. We are exploring the possibility of using ""aldehyde scavangers"" to ameliorate or prevent DOPAL-mediated toxicity (7)."
Date Last Modified: 04/12/2016 -
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