Newswise — Funding from The Michael J. Fox Foundation for Parkinson's Research will allow University of Alabama and University of Alabama at Birmingham researchers to further study a promising lead in efforts to treat and prevent Parkinson's disease.
Drs. Guy and Kim Caldwell, professors in biological sciences at UA, and Dr. David Standaert, vice chair of neurology at UAB, will be awarded $250,000 to be split between the two research labs over the next two years, the Foundation announced July 11.
"We are extremely honored to be representing the goals of MJFF once again," said Guy Caldwell. "There is really a fine nucleus of Parkinson's researchers that has grown here in Alabama."
The award to the Alabama researchers was one of only 9 in the world made under the Foundation's Target Validation 2007 initiative and provides the state's researchers an opportunity to expand upon discoveries made in the Caldwell Lab under the Fox Foundation's 2003 Protein Degradation program.
In that earlier study, UA researchers pinpointed a protein, known as VPS41, for its effectiveness in preventing neurons which produce dopamine within the brains of the animal model, C. elegans, from dying. In Parkinson's patients, the death of dopamine neurons leads to the disease's trademark symptoms, rigid and tremoring limbs, difficulty in movement and impaired reflexes.
Under the new grant, the UA researchers will seek to determine which specific components of the protein are neuroprotective and how, and what regions of the protein might best be targeted for enhancement through drug therapy. UAB researchers will translate the findings from the tiny worm model, C. elegans, into mammalian models and human cell lines to see if the observed protective ability of VPS41 holds up in the more advanced biological systems and factors associated with Parkinson's.
Using the comma sized worm as an animal model gives scientists the ability to quickly and economically narrow genetic leads in the study of disease, Guy Caldwell said.
In the Caldwell Lab, doctoral student Shu Hamamichi, using a technique known as RNA interference, or RNAi, removed, one at a time, the functions of about 1,000 genes from the tiny nematode model to study the impact the missing function would have on cellular processes.
"Shu has done what can only be called a heroic effort of knocking out close to 1,000 genes in C. elegans in two years," Caldwell said. "If you were to do this in a mouse model for just a single gene, it would cost you close to $100,000 and nearly a year of work," Caldwell said.
From there, with the assistance of UA undergraduate biology majors, Adam Knight and Renee Rivas, Hamamichi took the most promising genes and gave cells more of them, a technique they refer to as over expressing, while watching for indications that specific genes were offering protection against protein misfolding.
Scientists have learned that people with too many copies of the code for another protein, alpha-synuclein, within their DNA will contract Parkinson's. Extra copies of this code can lead to repeated protein misfolding and death of the dopamine producing neurons. So, finding leads such as VPS41, or genes that make other proteins that are involved in, or can prevent, protein misfolding, is exciting, Caldwell said.
"Our effort is not limited to this gene, alone," Caldwell says of the gene that makes VPS41. The UA lab has identified a still growing list of genes that appear to be neuroprotective, at least in worms.
"We believe our list of genes represent the single largest collection of potential Parkinson's markers that have been identified thus far. Lots of people make lists of candidate markers based on genetic association, but no one has functionally looked at the ability of the gene to protect dopamine neurons from dying. And, here we have a group of them that have been identified on a functional basis. Granted, it's all in a worm."
Despite its simplicity, the worm has key neurotransmitters, like dopamine. And more than 50 percent of all human hereditary diseases have been linked to genetic components also found in the worm, so it's frequently used by scientists as a model on which to study human diseases. The 2006 Nobel Prize in Physiology or Medicine was awarded to a pair of worm researchers for their discovery, first published in 1998, of the RNAi technique now commonly used in the Caldwell Lab.
The Michael J. Fox Foundation is dedicated to ensuring the development of a cure for Parkinson's disease within this decade through an aggressively funded research agenda. Founded in 2000, the Foundation has funded or directed over $94 million in research to date. For more information, visit http://www.michaeljfox.org
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