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Researchers Identify Enzymatic Activity of Neurological Disease Gene


Opening a window to understand the molecular basis of a hereditary ataxia, Dartmouth Medical School researchers have identified an enzyme activity that is inactivated in all reported mutant forms of a disease protein. The discovery may lead to therapies to treat the neurological disease. The study appears in the June 3, 2005 issue of the Journal of Biological Chemistry (JBC) as Paper of the Week, an honor conferred on approximately 1% of JBC’s 6600 annual publications.

Dr. Charles BrennerMutations in the gene encoding Aprataxin are the second leading cause of an early onset hereditary ataxia termed ataxia-oculomotor apraxia 1. Early onset ataxias are progressive, neurological disorders, with the patients losing balance and motor coordination in their hands and legs, and suffering from other symptoms such as controlling ocular movements.

"As with many diseases for which genes were identified by positional cloning, one begins with insufficient information about the encoded protein that would allow one to formulate a disease hypothesis, let alone develop potential therapeutic strategies," said lead author Dr. Charles Brenner, associate professor of genetics and of biochemistry at Dartmouth Medical School.

By establishing that Aprataxin has an enzymatic activity, Brenner said, researchers can focus attention on potential Aprataxin target proteins that might be regulated by this gene. "Though we don’t think we can reverse the disease by putting the Aprataxin gene back in, we think we might be able to improve the functions of target proteins once we understand their roles and the consequences of their regulation by Aprataxin. In this way, the enzymatic activity of Aprataxin takes us to Aprataxin target proteins and potential therapeutic strategies," said Brenner, also senior editor of the book "Oncogenomics: Molecular Approaches to Cancer."

Working with Drs. Heather F. Seidle and Pawel Bieganowski, two post-doctoral fellows at Dartmouth’s Norris Cotton Cancer Center, Brenner recognized Aprataxin as having a protein domain related to "Hint," an enzyme they previously characterized. A large number of proteins function by modifying the structures of other proteins. Hint is an AMP-lysine hydrolase, meaning that it has the ability to remove a nucleotide modification, typically AMP, from a lysine sidechain. In earlier work with Dennis Wright, associate professor of chemistry at Dartmouth, and Konrad Howitz of Biomol, Inc., Brenner and co-workers developed a synthetic chemical substrate that allowed Hint to produce a strong fluorescent signal when it did its job (AMP-lysine hydrolysis) on a model compound.

In this study, the researchers purified human Aprataxin and every disease-associated mutant form of Aprataxin and measured the ability of these proteins to function as AMP-lysine hydrolases. Though the model substrate may not have all of the features Aprataxin is looking for in a substrate inside the cell, the authors showed that wild-type Aprataxin possessed AMP-lysine hydrolase activity that depends on its Hint active site and that all disease-associated mutant forms of Aprataxin reduced or eliminated this activity. The next step, according to Dr. Seidle, is to identify the protein targets in vivo.

Andy Nordhoff | EurekAlert!
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