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Chemical chaperone could open door to treatment of neurological disorder
Date:2/5/2008

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Niemann-Pick type C disease is a recessive inherited trait that can originate in one of more than 200 different mutations in the NPC1 gene, which lies on chromosome 18. The mutations lead to production of abnormal NPC1 protein. Normally, NPC1 protein plays an essential role in moving cholesterol out of cells, and if it doesn't function, cholesterol and other lipids accumulate.

Most scientists assumed that Niemann-Pick type C mutations produced NPC1 protein that didn't work correctly. So when a routine test in the Ory lab of a mutated NPC1 protein showed that the protein was in fact active in living cells, the researchers did a double take.

"It is unequivocal that the mutation causes disease in human patients," says Ory, also associate professor of cell biology and physiology. "Yet the mutated protein seemed functional when we introduced it into cells."

When they looked for the explanation for this aberration, Ory and colleagues found that a small proportion of the mutant protein actually could do the job of normal NPC1 protein. It turned out that the mutation caused most newly minted NPC1 protein molecules to fold into the wrong shape or to assume their final shape slowly so that the cell's quality control checkpoints rejected them. But some of the mutant protein molecules assumed the correct shape and made it to their proper destination.

That suggested to the team that Niemann-Pick type C disease possibly could be treated with chemicals that assist the mutant proteins produced in patients. Ory refers to these as chemical chaperones and indicates this approach could help the large NPC1 proteins during the process of folding their long, complex chains so that more of the mutant proteins fold properly and pass through the cell's quality control checkpoints.

In collaboration with the National Institutes of Health Chemical Genomics Center, Ory will next screen more than 200,000 compounds to see which ones increase
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Contact: Gwen Ericson
ericsong@wustl.edu
314-286-0141
Washington University School of Medicine
Source:Eurekalert  

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