Professor Yoon Ki Kim’s research team discovers the formation pathway of abnormal proteins that cause alzheimer’s.
They are the first to determine how the formation of cytoplasmic aggregates of abnormal protein can be controlled through the CTIF protein. 

▲ Prof. Yoon Ki Kim, School of Life Sciences, College of Life Sciences and Biotechnology 

A clue that sheds light on how masses of protein (aggregate) that appear in neurodegenerative diseases such as Alzheimer’s are formed is making headlines. 

The research team led by Professor Yoon Ki Kim of the School of Life Sciences under the College of Life Sciences and Biotechnology is the first to determine that abnormal proteins created within cells, along with normal proteins, can be controlled through the CTIF* protein and that it is this protein that determines the formation path of aggregates.

 * Aggregate: A formation observed in the brains of neurodegenerative disease patients, it is a place where abnormal proteins accumulate. From the cell-level, they are known to have a similar biochemical and morphological format with that of aggresomes.

 * Initiation Factor: protein factor involved in protein synthesis initiation 
 * CTIF (CBP80/20-dependent translation initiation factor): a type of protein translation initiation factor

Research was performed under sponsorship of the Ministry of Science & ICT, National Research Foundation of Korea as part of the Fundamental Research Project (Individual Research) and the results were published in the June 8th edition of the international scientific journal, Nature Communications.

 - Title of the Article: Misfolded polypeptides are selectively recognized and transported toward aggresomes by a CED complex
 - Author Information: Professor Yoon Ki Kim (Corresponding Author, Korea University), Joori Park (Co-Primary Author, Korea University), Yeonkyoung Park (Co-Primary Author, Korea University)

Throughout its lifespan, new proteins are continuously created in and disappear from the human body. Normal proteins are created, but abnormal proteins are created as well. Usually, abnormal proteins disappear as a result of autophagocytosis. However, if abnormal proteins were to accumulate, it could cause various illnesses. The surveillance pathway of abnormal proteins has yet to be accurately proven.

The research team was able to determine that the CTIF proteins exist in the aggregate frequently observed in the brains of neurodegenerative disease patients and that there existed a place (aggresome) where abnormal proteins accumulated. If CTIF were not present, abnormal protein did not accumulate. This shows that the CTIF protein is the key protein to controlling abnormal proteins.

Resulting from the research of the abnormal protein surveillance pathway, the team was able to determine that immunoprecipitation reaction showed that the CTIF protein interacted with the previously known dynactin1 and eEF1A1 to form a complex. This complex recognizes the abnormal protein and takes on the role of transporting the abnormal protein to the aggresome.

* Immunoprecipitation Reaction: A method to extract the target antigen and the proteins that colligates with it by immersing and retrieving a complex created as a result of coupling a specific antibody to a target antigen.

* dynactin1: A combination of microtubule and dynein that serves as a medium to transport material.
* eEF1A1: A translation elongation factor used in eukaryotes. It creates aggresome formation signals.  

Upon examining the brain tissues of Parkinson’s patients, the team could see that CTIF accumulated in the aggregate of the brain cells. CTIF was located in the same position as specific material (α -synuclein) observed in Parkinson’s patients. This indicates that the CTIF protein selectively recognizes abnormal protein through dynactin1 and eEF1A1 and takes on the role of transporting the abnormal protein to the aggresome. 

 * α-synuclein: A peptide made up of 140 amino acids. Normally exists as a monomer in black matter, hypothalamus, and nervous system neurons.  When it is not correctly decomposed, it builds up in an accumulative form and destroys neurons. It is mainly found in the brain tissue of neurodegenerative disease patients.

Professor Kim commented on the significance of the research by stating, “This research is the first report to determine that the aggregate formation of abnormal proteins can be controlled through the CTIF protein. I am hopeful that this will contribute to the development of medicines for neurodegenerative diseases including Alzheimer’s and Parkinson’s.”

[ Terminology ]

1. Nature Communications
 ○ World-renowned life sciences journal with a Citation Index of 12.124. 

2. CTIF (CBP80/20-dependent translation initiation factor) 
 ○ A type of protein translation initiation factor.
 ○ A protein well-known for playing an important role in the verification mechanics of the quality of mRNA.

3. Dynactin 1
 ○ Combination of microtubules and dynein, medium to transport material. 

4. eEF1A1
 ○ A translation elongation factor used in eukaryotes. Creates aggresome formation signals. 

[ Figure Description ]

Figure 1: Proof of the existence of the CTIF protein within the aggregate existing in Parkinson’s disease patients’ brain tissue.
By using the immunohistochemical technique, the research team observed that the α-synuclein aggregate existing in the brain tissue of Parkinson’s disease patients and the CTIF protein were located in the same location. This means that the CTIF protein is involved in the formation of abnormal protein aggregates in neurodegenerative disease patients.

Figure 2: Misfolded protein removal mechanism through the CTIF protein.
If misfolded protein accumulates in the cell, the CTIF-dynactin1–eEF1A1 complex recognizes the misfolded protein, and then the complex moves the misfolded protein to a large protein aggregate called an aggresome. The formed aggresome consequently gets removed from the cell by the lysosome. Through this mechanism, misfolded proteins can be continuously removed from the cell. It is known that if this mechanism does not operate properly, it is directly related to the pathogenesis of neurodegenerative diseases.