Huntington’s disease is a brain disorder that occurs when an abnormally folded huntingtin protein accumulates and forms aggregates. This disease tends to occur in middle adulthood (mid 30s to mid 40s) and causes a loss of muscle coordination and eventually psychiatric symptoms as well as a loss in memory. According to the Huntington Disease Society of America, the average lifespan after onset of the disease is 10-20 years.
In the cytosolic space of eukaryotic cells, there is a protein referred to as TriC, which is part of an aggregate that acts as a chaperonin. Chaperonins are molecules that assist in the proper folding of other proteins. TRiC has been demonstrated to be able to inhibit the aggregation of mutant huntingtin proteins. Researchers from Baylor College of Medicine (BCM) and Stanford University in California have been able to elucidate this process. Their findings are available in the open access journal eLife.
Dr. Wah Chiu, professor of biochemistry and molecular biology at BCM, and his team have identified how TriC inhibits aggregation of this mutant protein by using cryo-electron tomography, three-dimensional mapping and computer-aided reconstruction. Chiu’s background includes serving as director of the National Center for Macromolecular Imaging at BCM and the Center for Protein Folding Machinery. Chiu is also co-director of the W. M. Keck Center for Computational Biology.
Huntington’s disease falls into the category of what is referred to as trinucleotide repeat disorders. This means that there are three nucleotides in a particular gene sequence that repeats itself more than it should and in this case it happens to be a CAG sequence. CAG happens to code for the amino acid glutamine and this sequence repeats for more than 36 times. This causes the huntingtin protein to aggregate forming large clusters of fibrils.
The researchers demonstrated that TRiC has the ability to sequester soluble huntingtin proteins and prevent them from forming aggregates. Furthermore, they observed a separate population of TriC that has the ability to cap the tips of the fibrils preventing them from elongating into larger aggregates.
As Chiu points out, “TRiC is a protein machine that is shaped like a beer barrel with two chambers. When the protein comes from the ribosome (the protein-making part of the cell), it is drawn into the barrel and that environment helps to fold it correctly. Many major cellular components require this TRiC to attain their proper shape to function properly, and without TRiC, we would all be dead.”
Next on the agenda is to see if a drug can be made to prevent huntingtin protein aggregation. Chiu indicates that his team wants to find the smallest piece of the TRiC chaperonin that can do what the whole protein can do. He goes on further to say that they have learned that it is equally important to see how a protein works as well as looking at its gene.
For more information about research at Baylor College of Medicine, visit www.bcm.edu/fromthelab.