Investigational protein may reverse neurodegenerative diseases

An investigational protein that transformed normal laboratory mice into super-jocks holds great promise in developing new treatments for neurodegenerative diseases like Parkinson's, Alzheimer's and ALS (Lou Gehrig's Disease), say researchers at the University of Virginia Health System.

A study published in the February 17, 2009 online edition of Mitochondrion reports that the protein, rhTFAM (an abbreviation for recombinant-human mitochondrial transcription factor A), succeeded in entering and energizing the DNA of the mice's mitochondria, enabling them to run two times longer on their rotating rods than a control group cohort.

Because many neurodegenerative diseases cause mitochondria to malfunction, medical researchers have been focusing on developing methods for repairing and restoring them. The new UVA study represents an important step toward achieving that goal. It shows that a naturally occurring protein, TFAM, can be engineered to rapidly pass through cell membranes and target mitochondria. Study findings show that rhTFAM acts on cultured cells carrying a mitochondrial DNA disease as well as lab mice.

Conducted in conjunction with Gencia Corporation, a Charlottesville-based biotechnology firm that owns rhTFAM, the study also describes a scalable method of producing the protein in needed quantities.

Mitochondria are the cellular engines that transform food into fuel in our bodies and perform their work in the energy-intensive tissue of our brains, retinas, hearts and skeletal muscles. When damaged, mitochondria slow down, stop generating energy effectively and begin to over-produce oxygen free radicals. If produced in excess, oxygen free radicals chemically attack all cell components, including proteins, DNA and lipids in cell membranes.

"In simple terms, an overabundance of these free radicals cause cells to start rusting," notes lead study author James P. Bennett, Jr., M.D., PhD, a professor of neurology and psychiatric research at the UVA School of Medicine and director of its Center for the Study of Neurodegenerative Diseases.

While the UVA findings are preliminary, Bennett considers them encouraging. "We've shown that the human mitochondrial genome can be manipulated from outside the cell to change expression and increase mitochondrial energy production," he notes. "This is arguably the most essential physiological role of the mitochondria."

Although important questions remain about the technology, mechanisms and therapeutic potential of rhTFAM, Bennett believes his team's findings could contribute to the development of treatments that repair and restore damaged mitochondria in cells. "We're looking toward the day when we can reverse or delay the progression of various neurodegenerative diseases and other conditions where cell energy production is deficient, including cancer, diabetes and aging," he says.

Gencia made rhTFAM available to UVA under a material transfer agreement. One study author, Francisco R. Portell, has an affiliation with the company.

Study authors also include Shilpa Iyer, Ravindar R. Thomas, Lisa D. Dunham and Caitlin K. Quigley. All work at the Center for the Study of Neurodegenerative Diseases and the Morris K. Udall Parkinson's Disease Research Center of Excellence at UVA.

Related link: Recombinant Mitochondrial Transcription Factor A with N-terminal Mitochondrial Transduction Domain Increases Respiration and Mitochondrial Gene Expression - http://www.sciencedirect.com/science/article/B6W8G-4VJ09B8-1/2/c6ae1ad2860553ca6286e9fe71d9e144