News Release

Protein "Chaperone" Interactions Found to Play Major Role in Cystic Fibrosis

Findings May Point to New Treatment Options for Numerous Diseases

LA JOLLA, CA, November 16, 2006—Scientists at The Scripps Research Institute have described for the first time key protein interactions that contribute to the development of cystic fibrosis. These findings may provide a new framework for the correction of cystic fibrosis and other protein folding diseases.

The study, led by Scripps Research Professor William Balch, Ph.D., is being published on November 17 in the journal Cell.

Cystic fibrosis is an inherited disease, whose primary symptom is abnormally thick mucus that blocks airways and causes difficulty breathing. Other symptoms include incapacitating lung infections, intestinal disorders, diabetes, and infertility. About 30,000 people in the United States have cystic fibrosis, according to the Cystic Fibrosis Foundation. An additional 10 million more—or about one in every 31 Americans—are carriers of the defective gene, but do not have the disease.

Cystic fibrosis is triggered by a genetic mutation that causes the defective folding and retention of a specific protein in the endoplasmic reticulum, the part of the cell used for protein translation, folding, and for preparation for transport to the surface of the cell. Normally, this essential protein—called cystic fibrosis transmembrane conductance regulator (CFTR)—acts as a membrane channel for control of movement of sodium and chloride ions (typically found in salt) between the inside and outside of the cell. The correct salt balance across the cell surface is critical for water balance throughout the body.

A mutation in the CFTR gene can result in the failure of the CFTR protein to reach its normal position on the apical or top surface of epithelial cells lining the lung, intestine, and pancreas. The lack of the proper water balance then results in the failure of the thick mucus deposited on the outside of these cells to become properly hydrated, leading to severe lung and tissue dysfunction.

In the new study, the scientists used mass spectrometry and multi-dimensional protein identification technology to describe how the heat shock protein Hsp90 and other molecular chaperones and co-chaperones (chaperone helpers) control the stability of the critical CFTR protein. Molecular chaperones are proteins that assist other proteins in achieving proper folding. Earlier studies by the Balch and Kelly groups at Scripps Research raised the possibility that the chaperone environment might play a critical role in establishing a diverse range of stabilities that  efficiently support the export of both soluble and membrane anchored cargo such as CFTR to the cell surface, a conclusion that now appears to be confirmed by the results of this latest research.

While more than 1,500 different mutations of the cystic fibrosis gene have been found, the dF508 mutation is the most common, occurring in approximately 70 percent of all cases of cystic fibrosis, according to the National Institute of Diabetes & Digestive & Kidney Diseases. Importantly, in the study the scientists were able to reverse the disease process in cell culture for the dF508 mutation by partial siRNA silencing of the Hsp90 co-chaperone ATPase regulator Aha1.

"We found that changes in the Hsp90 co-chaperone folding environment dramatically altered the stability and export of the misfolded dF508 CFTR protein from the endoplasmic reticulum," said Balch. "These findings are consistent with the view that the cellular chaperone pool does not simply prevent aggregation, but can regulate specific cellular protein folding pathways, controlling the success or failure of the protein fold, even misfolded proteins, for function and export."

"The study's identification of the interactions that contribute to CFTR folding should play a pivotal role in any future study of the molecular basis for the disease," Balch continued. "In addition, the research points to Hsp90 and its co-chaperones as possible therapeutic targets, meaning that we may have the potential to control misfolding diseases like cystic fibrosis. In fact, by focusing on correcting the protein fold, we may be able to inhibit many of the later interactions that contribute to the pathology of cystic fibrosis and other terrible diseases."

In addition to cystic fibrosis, protein-folding diseases include Alzheimer's disease,Parkinson's disease, Creutzfeldt–Jakobdisease, Huntington's disease, and Gaucher's disease, among other disorders.

In addition to Balch, authors of the study, "Hsp90 Co-Chaperone Aha1 Downregulation Rescues Misfolding of CFTR in Cystic Fibrosis," include Xiaodong Wang, John Venable, Paul LaPointe, Darren M. Hutt, Atanas V. Koulov, Judith Coppinger, Cemal Gurkan, Wendy Kellner, Jeanne Matteson, Helen Plutner, and John R. Yates III of The Scripps Research Institute; Jeffrey W. Kelly of The Scripps Research Institute and The Skaggs Institute for Chemical Biology; and John R. Riordan of the University of North Carolina.

This work was supported by the National Institutes of Health and the Cystic Fibrosis Foundation.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.

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