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Investigational protein related to mitochrondrial function may hold hope for ALS cure
by Jeffrey Bouley  |  Email the author

CHARLOTTESVILLE, Va.—Researchers at the University of Virginia Health System report that they have an investigational protein that can not only transform normal laboratory mice into "super-jocks," but may, more importantly, hold the key to potential therapies that could effectively treat—and perhaps even reverse—neurodegenerative conditions like Parkinson's disease, Alzheimer's disease and Lou Gehrig's disease.

Publishing their findings with the journal Mitochondrion, which posted the article online in mid-February, the team says that the protein, recombinant-human mitochondrial transcription factor A (rhTFAM), not only successfully entered the DNA of the mice's mitochondria but also "energized" them, enabling them to run two times longer on their rotating rods than could mice in a control group.

This is important, the researchers say, because many neurodegenerative diseases cause mitochondria to malfunction, and they and other researchers therefore have been focusing on finding ways to repair mitochondria and restore their function. The University of Virginia study suggests that the naturally occurring protein TFAM can be engineered to rapidly pass through cell membranes and target mitochondria.

In addition to testing this theory with mice, the researchers showed that rhTFAM also acts on cultured cells carrying a mitochondrial DNA disease.

"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," says Dr. James P. Bennett Jr., director of the University of Virginia School of Medicine's Center for the Study of Neurodegenerative Diseases and a professor of neurology and psychiatric research at the school.

Given that the potential applications are so broad, why focus on neurodegenerative disease?

"In the drug development process, you really need to pick one thing to focus on, and then as you show some value for one disease, you can get the FDA to be more amenable to other disease targets," notes Bennett, the lead author for the study. "It seemed to us that the best place to focus our efforts on—and the place where we were most likely to see success—was in the neurodegenerative area, specifically amyotrophic lateral sclerosis, or ALS, which is Lou Gehrig's disease."

In explaining the importance of this area of study, the University of Virginia team notes that mitochondria are the cellular engines that transform food into fuel, performing 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," Bennett says. He adds, though, that the study findings are preliminary and much work remains on the way to a therapeutic compound. "However, we've shown that the human mitochondrial genome can be manipulated from outside the cell to change expression and increase mitochondrial energy production, and this is arguably the most essential physiological role of the mitochondria."

Three key areas remain to be tackled, the research team noted in its paper. First, it is not known if exogenous TFAM that has migrated to the mitochondrial compartment has the same intra-mitochondrial localization as endogenous TFAM, which is believed to complex with mitochondrial DNA and multiple other proteins in mtDNA-protein complexes known as nucleoids. Although the team's observations suggest that exogenous TFAM is capable of entering the matrix and nucleoids and positively regulating mitochondrial transcription and replication, this effect has not yet been proven.

Second, because TFAM enters the mitochondrial compartment within minutes, it is unclear to the researchers why there is a one- to two-week interval between TFAM exposure and increases in mitochondrial gene expression and respiration, and they have studies underway to address this question.

Third, the team was surprised to find an apparent global increase in mitochondrial electron transfer chain protein expression and they say that further investigation is required on how exposure to a single mitochondrial DNA transcription factor can potentially activate a complex mitochondrial biogenesis program.

The study was conducted in conjunction with Gencia Corp., a Charlottesville-based biotechnology firm that owns rhTFAM, and which made rhTFAM available to the university under a material transfer agreement. One study author, Francisco R. Portell, has an affiliation with the company, though none of the authors have a financial stake in the company.

In addition to Bennett, the other study authors for "Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression" include: Shilpa Iyer, Ravindar R. Thomas, Lisa D. Dunham and Caitlin K. Quigley.



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