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Determination of Huntington's disease Protein

Study on the 3D Structure of the Huntington Protein Using Electron Microscopy

Huntington’s disease, also known as Huntington’s chorea, is a type of degenerative brain disease that occurs due to the expansion of polyglutamine at the amino terminus of the Huntingtin protein, which causes problems with the autonomic nervous system. Symptoms of the disease include jerky dancelike movements of the hands and feet. Huntington’s disease, whose symptoms usually begin between 30 and 50 years of age, is a dominant genetic disease caused by a gene on chromosome 4. The disease often results in unstable gait due to lack of coordination and problems with mental abilities. In severe cases, physical abilities begin to deteriorate and symptoms of dementia develop. The first evidence of neurodegeneration is damage to neurons, which results in the partial elimination of inhibitory signals transmitted to the premotor and supplementary motor areas of the frontal lobe, causing jerky body movements. As Huntington’s disease continues, neural degeneration is found in other areas of the brain, including the cerebral cortex.

A study conducted in 1993 found that Huntington’s degenerative brain disease was caused by a expansion of polyglutamine in the Huntingtin protein. The Huntingtin protein is very large in size, consisting of more than 3,000 amino acids, and it has never been studied previously for its molecular structure or biochemistry. In 2005, however, professor Ji-Joon Song of KAIST, who is specialized in protein structure determination, started his research jointly with professor Ihn-Sik Seong of Harvard Medical School, an expert on Huntington’s disease. Based on their joint research, in 2010, they succeeded in producing the ful-length Huntingtin protein for the first time in the world, and published a paper on its structural and biochemical functions. The joint research continued after professor Song was appointed to KAIST in 2009, and professor Seong at Harvard Medical School in 2012. A breakthrough in the research came when professor Ji-Joon Song joined, during his sabbatical year in 2013, professor Hans Hebert’s research group at Karolinska Institutet in Sweden, an institution in charge of selecting the Nobel Prize in Physiology or Medicine. While working to analyze protein structures using an electron microscope, he determined the 3D structure of the Huntingtin protein and successfully concluded his research in close collaboration with the research team of professor Seong at Harvard Medical School. “Previously, the impacts of polyglutamine expansion, which causes the disease, on the Huntingtin protein were not clear, and the biochemical properties of the Huntingtin protein were not known either. And this was the area we decided to focus our research on. In this study, we used a transmission electron microscope to produce a 3D structure of the protein using shapes gained by transmitting protein samples and projecting the resulting shapes.”

Determining the Cause of the Disease by Analyzing Polyglutamine Expansion

Polyglutamine, which consists of glutamine amino acids linked in succession, has not been studied for its effects even though its expansion is known to be a cause of many degenerative brain diseases. In recognition of this, in their study, the authors aimed to analyze the entire Huntingtin protein, which is affected by polyglutamine expansion, for the first time in the world, in order to understand the impacts of the expansion on the amino terminus. The authors found that the huge Huntingtin protein consists of five domains and has a circular shape due to the phenomenon of protein folding. In particular, they explained that the increase in the length of the polyglutamine at the amino terminus of the Huntingtin protein leads to changes in its entire structure. Through this study, the research team of professor Ji-Joon Song has paved the way for the development of a treatment regimen for Huntington’s disease, and helped to explain the mechanisms behind degenerative brain diseases caused by polyglutamine expansion, like ataxia. Going forward, the research team aims to demonstrate the 3D structure of the entire Huntingtin protein at atomic-level resolution, and develop a treatment for Huntington’s disease. The study was conducted through multi-national collaboration, applying various methodologies of various research groups in Korea, the U.S., Sweden, Switzerland, etc. The findings of the study were published in eLife, a prestigious journal on molecular biology, jointly issued by Germany (Max Planck Institute), the U.S. (Howard Hughes Medical Institute), and the U.K. (Wellcome Trust)

Prof. Song, Ji-Joon
2016 Annual Report

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