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Formation and Re-formation of the Complex of the Disease-related Polyglutamine Proteins, ATXN1 and Capicua

Opening a new prospect for the treatment of neurodegenerative disease

"The AXH domain of ATXN1 and Capicua (CIC) complex structure was determined, revealing the mechanism for the complex formation between the polyglutamine neurodegerative disease protein and transcriptional repressor. It has been suggested that the complex formation of ATXN1 and CIC might be implicated in the occurrence of spinocerebellar Ataxin Type 1 (SCA1) neurodegenerative disease. The current research is significant in that it has provided the molecular target for the development of a cure for the degenerative brain disease."

Providing clues to the causes of degenerative brain disease

Degenerative brain diseases are often represented by Alzheimer’s disease, which is known to cause dementia. Such a disease gradually worsens over a period of 10 years from its onset. Because of this feature, degenerative brain disease greatly influences not only the patient and his or her family but also the society as a whole. However, there have not been enough studies to understand the molecular mechanisms that cause degenerative brain disease. Also, there has not been any effective medicine for such a disease. Among various types of degenerative brain disease, there is polyglutamine degenerative brain disease, which occurs due to the expansion of polyglutamine in protein.

Polyglutamine degenerative brain disease is an autosomal dominant gene-based nerve disorder that occurs due to the expansion of the repetitive sequence of glutamine amino acids to the protein causing the disease. So far, a total of nine polyglutamine diseases have been found. The representative disorders include Spinocerebellar Ataxia and Huntington’s disease. In terms of polyglutamine degenerative brain diseases, the KIB research team, led by Professor Ji-Joon Song, has found the process of complex formation of ATAXN1, which is responsible for SCA1 (Spinocerebellar Ataxia Type 1).

Professor Song’s team focuses the proteins, ATXN1 and Capicua (CIC), which influence the occurrence of Spinocerebellar Ataxia. ATXN1 is a protein that can be found throughout the whole body, but its function is not known. However, when polyglutamine expansion occurs in ATXN1, it influences a specific part of the brain, causing the degenerative brain disease. In order to find out the mechanism for the complex formation of ATXN1 and Capicua, Professor Song’s team carried out research for four years from the beginning of 2009 to the spring of 2013.

ATXN1 is known to interact with several proteins. Among them, the transcription repressor protein of Capicua is known to interact with the AXH domain of ATXN1 within the cell nucleus. Such complex formation might be responsible for causing the degenerative brain disease, Spinocerebellar Ataxia Type 1-SCA1. People suffering from the disease have problems swallowing food and retracting their eyebrows, which causes them to fixate their gaze on one point. They also experience loss of verbal and time memories.

Dr. Song’s team carried out research to figure out the mechanism for the formation of the complex between the polyglutamine disease-related proteins of ATXN1 and Capicua, which could be regarded as the first fundamental stage for the treatment of degenerative brain disease. In order to figure out the mechanism for the combination of ATXN1 and Capicua, the research team found the 3D atomic structure of the combined state of ATXN1 and Capicua by using the X-ray crystallographic method.

As a result, the research team revealed that during the process of forming ATXN1 and Capicua complex ATXN1-ATXN1 dimer complex dissociate upon binding with Capicua. Furthermore, ATXN1-Capicua complex makes another form of the tetramer of ATXN1-Capicua-Capicua-ATXN1. It was reported that, by hindering the combination of the two proteins, it would be possible to improve the symptoms of degenerative brain disease. Therefore, by using such a research result, the base for the development of a medicine that could hinder the complex formation of ATXN1 and Capicua was established. Certainly, it would take decades to develop an actual medicine that could be used to treat degenerative brain disease based on this research. However, the research team led by Professor Ji-Joon Song clarified the mechanism of the complex formation of the protein causing degenerative brain disease. Moreover, the research team provided new targets for the treatment of the degenerative brain disease, opening a new prospect for the understanding of degenerative brain disease at the molecular level.

Prof. Song, Ji-Joon
2013 Annual Report

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