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Preventing protein aggregation in Huntington’s disease requires special TRiC

Huntington's disease is a devastating neurological disorder that occurs when a defective huntingtin protein forms aggregates that somehow affect brain function. In mid-adulthood, those who have the disease lose muscle coordination and go on to develop psychiatric symptoms, lose the ability to remember and think clearly. They die much too early.

Inside cells a protein called TRiC, which assists in the protein folding process, has been shown to inhibit the aggregation of the mutant huntingtin proteins. Now, a group of researchers from Baylor College of Medicine and Stanford University in California have found out how it accomplishes that task. They describe their research online in the open access journal eLife.

Using cryo-electron tomography combined with three-dimensional mapping and computer-aided reconstruction, the team, led by Dr. Wah Chiu, professor of biochemistry and molecular biology at BCM, and first authors, Sarah H. Shahmoradian and Jesus G. Galaz-Montoya of BCM, have identified how TRiC inhibits aggregation of the mutant huntingtin protein. (Chiu is also director of the National Center for Macromolecular Imaging at BCM and the Center for Protein Folding Machinery. He is co-director of the W.M. Keck Center for Computational Biology.)

Trinucleotide repeat disorder

Huntington’s disease is one of many so-called trinucleotide repeat disorders, in which three nucleotides in the gene sequence repeat an abnormal number of times. In Huntington’s, the nucleotide sequence CAG, which encodes for the amino acid glutamine, repeats more than 36 times, prompting formation of aggregates of the protein in the brain of patients with Huntington’s. This aggregation occurs when soluble precursors to the protein - called oligomers combine to form structure called fibrils. These fibrils assemble into the larger clusters or aggregates.

The BCM-led team showed that in the presence of mutant huntingtin protein, TRiC sequesters the soluble huntingtin molecules to prevent them from joining together, while a separate population of TRiC caps the tips of the fibrils, preventing them from elongating into larger aggregates.

"TRiC is a protein machine that is shaped like a beer barrel with two chambers," said Chiu. "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."

Cap and contain

"We call it 'cap and contain,' said Shahmoradian, one of the first authors who is now at Center for Cellular Imaging and Nano Analytics (C-CINA), department of biosystems science and engineering (d-bsse), structural biology and biophysics in Basel, Switzerland. "Not only does TRiC internalize these small fragments of the bad huntingtin protein and prevents them from associating together to become larger aggregates, it also caps the end of the fibrils."

"How can we make a drug to prevent aggregation?" Chiu said. "My team wants to find the smallest piece of TRiC that could basically do what the whole protein does. We’ve learned that looking at how the protein works is as important as looking at the gene."

Others who took part in the research include Michael F. Schmid, Yao Cong, Boxue Ma and Steven J. Ludtke, all of BCM and Christoph Spiess and Judith Frydman of Stanford.

Funding for this work came from the National Institutes of Health (Grants PN2EY016525, P41GM103832 and R01GM080139), the Nanobiology Interdisciplinary Graduate Training Program of the W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (NIH Grant T32EB009379).

Chiu is a Distinguished Service Professor at BCM and is the Alvin Romansky Professor of Biochemistry and Molecular Biology at the College.

For more information on research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab.