Research Progresses in Mitochondria Function

 Scientists know that Huntington's Disease is caused by an expansion of the CAG repeat, coding for the amino acid glutamine, in the gene that encodes the huntingtin protein. That is why HD is called a polyglutamine or CAG repeat disease. However the means by which this mutant protein causes degeneration remains unknown.

 In a study to be published in the August issue of Nature Neuroscience (and available online July 1), HDSA-funded Coalition for the Cure investigator, J. Timothy Greenamyre of Emory University in Atlanta GA found that the mutant protein disrupts the mitochondria of nerve cells in the brain. Mitochondria are the ‘power plants’ within each cell, which provide the energy necessary for all cell functions. They are the principal sites where energy is generated from the oxidation of food we ingest. This work was a collaboration between Emory investigators (Sasha Panov, Claire-Anne Gutekunst and Greenamyre), University of British Columbia scientist Michael Hayden (who also is an HDSA Coalition for the Cure investigator) and his colleague Blair Leavitt, and Duke University investigators James Burke and Warren Strittmatter.

 Mitochondria normally have a membrane potential, like the charge of a battery. Dr. Greenamyre and colleagues found that mitochondria from blood cells of people with HD have a lower membrane potential (“charge”) than normal. In addition, mitochondria normally take up calcium when it enters nerve cells and, in this way, prevent cell damage and death that may be caused by excessive calcium levels. The scientists found that HD mitochondria could not take up calcium as efficiently as normal mitochondria. To confirm that the same mitochondrial abnormality occurs in the brain, they also looked at brain mitochondria from genetically engineered mice, which have the mutation that causes HD. Brain mitochondria had a defect identical to the one seen in mitochondria from blood cells of people with HD. Furthermore, when the scientists added a synthetic, “mutant” polyglutamine-containing protein to normal mitochondria taken from people without HD, the mitochondria behaved like HD mitochondria. Therefore, the investigators concluded that mutant huntingtin protein has direct, harmful effects on mitochondria. Also, because the mitochondrial abnormalities occurred in mice very early – before there were other signs of disease – Dr. Greenamyre and his colleagues believe malfunctioning mitochondria may be very important in causing nerve cells to become dysfunctional and to eventually die.

 Take home message:

Dr. Greenamyre believes that understanding exactly how mutant huntingtin protein harms mitochondria may lead to new ways to protect the nerve cells that die in HD. And, if drugs can be found that improve mitochondrial function, they may be useful to slow or stop disease progression. It is also possible that these findings could help to explain why people with HD have difficulty gaining or retaining body weight despite eating high calorie diets.

Dr. Greenamyre will be honored on October 16 with the inaugural Team Hope Medical Leadership Award in recognition to his many contributions in both HD research and clinical care. Dr. Greenamyre is a founding member of the HDSA Coalition for the Cure and has played a significant role in both expanding HDSA's Grant and Fellowship program as well as the Center of Excellence at Emory.
If you would like more information about this honor, please contact Mary Beth Ford at mbford@hdsa-pgh.org.

Contact: Debra Lovecky
212-242-1968, ext. 28
dlovecky@hdsa.org