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Novel Small Protein Offers a Deeper Look at the Pathology of Alzheimer’s Disease
  • 작성일2022-01-12
  • 최종수정일2022-01-12
  • 담당부서연구기획과
  • 연락처043-719-8033

Novel Small Protein Offers a Deeper Look at the Pathology of Alzheimer’s Disease


The protein, a variant of a well-known tranion factor, blocks misfolded protein clearance in the brain, thus serving as an attractive drug target


The elimination and recycling of unnecessary cellular constituents, termed “autophagy,” is critical for the smooth functioning of cells and body organs such as the brain. However, when this process becomes defective, it leads to accumulation of misfolded proteins inside the brain. Now, researchers from Korea National Institute of Health have successfully cloned “small TFEB,” the truncated version of a regulatory protein involved in autophagy. They believe that small TFEB provides novel insights into Alzheimer’s disease pathology.


Newly discovered protein involved in cellular recycling processes plays a key role in neurodegeneration and might offer insights into the pathophysiology underlying Alzheimer’s Disease, state researchers from Korea National Institute of Health

Newly discovered protein involved in cellular recycling processes plays a key role in neurodegeneration and might offer insights into the pathophysiology underlying Alzheimer’s Disease, state researchers from Korea National Institute of Health.

Photo courtesy:  FGC from Shutterstock


Nature loves to recycle. Cells constantly eliminate unnecessary constituents like misfolded proteins and malfunctioning organelles by recycling them into useful raw material such as amino acids and lipids. This cellular recycling process, commonly known as autophagy, ensures the smooth functioning of various organs, including the human brain.


Several proteins are involved in the regulation of autophagy, such as tranion factor EB (TFEB-L), which is considered a master regulator of the important pathways in this cycle. However, the process is known to become defective during the early stages of neurodegeneration, and presumably contributes to the development of disorders such as Alzheimer’s disease.


To better understand how the process of autophagy ties into the pathology of neurodegenerative disorders, researchers from Korea National Institute of Health have recently successfully cloned and studied the function of small TFEB, which is a “splice variant”, or a truncated version of the full-length TFEB-L. The corresponding study, supported by a fund (2019-NI-086-02) received from the Korea Disease Control and Prevention Agency, has been published in the journal Scientific Reports. The proposed mechanism of action of small TFEB reveals interesting information on how the truncated protein likely inhibits the process of autophagy.


The team designed a series of experiments to determine small TFEB’s mechanism of action. First, they tried to experimentally detect the presence of small TFEB inside various human tissues. The results were promising: the presence of small TFEB was observed in several tissues, including those from the human brain. Quite interestingly, cells that were made to produce small TFEB showed a decrease in genes related to autophagy.

Overwhelming evidence supports a crucial role of genes from the autophagy-lysosomal pathway in the degradation of misfolded and aberrant proteins that accumulate in neurodegenerative diseases such as Alzheimer’s and Parkinson’s,” says first author Dr. JeeYun Park.         

Next, the researchers fluorescently tagged both TFEB-L and small TFEB to determine their respective locations inside T4 (neuronal) and HEK293 (kidney) cells. Under normal circumstances, TFEB-L was found to be present in the cellular cytoplasm. However, when mTORC1, the protein responsible for its localization, was blocked, TFEB-L moved from the cytoplasm into the nucleus. Interestingly, small TFEB also co-localized with TFEB-L inside the nucleus.

The team’s subsequent experiments showed that small TFEB not only localized, but also interacted with TFEB-L inside the cell nucleus.

To determine the precise role of this interaction, the researchers monitored the levels of a-synuclein and phosphorylated tau inside neuronal cells. Both these proteins are directly involved in neurodegenerative diseases. The most astonishing discovery soon followed: small TFEB was clearly causing a relative increase in the neuronal levels of both these pathogenic proteins!

The authors concluded that small TFEB’s mechanism of action presumably involved the blocking of the regulatory action of TFEB-L. Thus, this study has major implications in the area of Alzheimer’s disease research as it unravels a key mechanism in the neurodegenerative pathway.

According to Dr. Chulman Jo, corresponding author of the study and senior staff scientist at Korea National Institute of Health, “TFEB mainly takes part in the clearance of the toxic tau species. Its aggregation is a main pathology in Alzheimer’s disease. We discovered a novel alternative splicing variant of TFEB and revealed its function. Given that TFEB mainly takes part in the clearance of phosphorylated tau, small TFEB might be a promising therapeutic target for Alzheimer’s disease.

To sum up: This small protein holds huge implications for future research on neurodegenerative disorders!

Reference

Authors

JeeYun Park, HeeYoung Sohn, Young Ho Koh & Chulman Jo

Title of original paper

A splicing variant of TFEB negatively regulates the TFEBautophagy pathway

Journal

Scientific Reports

DOI

10.1038/s41598-021-00613-y 

Affiliations

Division of Brain Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Cheongju-si, 28159, Chungcheongbuk-do, Korea


About National Institute of Health in Korea 

The Korea National Institute of Health (KNIH), one of the major operating components of the Ministry of Health and Welfare, leads the nation’s medical research. Over the past seven decades, the KNIH has made unwavering efforts to enhance the public’s health and innovate biomedical research. The KNIH seeks to eradicate diseases and make people healthier. The KNIH establishes a scientific basis and evidence underlying health policy as well as provides national research infrastructures. We also promote public health research. To this end, we make efforts to enrich a health research environment by granting funds to research projects and keeping our resources, data, and facilities more open and accessible to researchers.

Website: http://www.nih.go.kr/NIH_ENG/


About Dr. Chulman Jo

Dr. Chulman Jo is a senior staff scientist working in the Division of Brain Disease Research at the Korea National Institute of Health. His research group is currently studying the molecular risk factors for tau pathology in Alzheimer’s disease. Dr. Jo completed his postdoctoral training in Dr. Gail Johnson’s laboratory at the Rochester University Medical Center, New York, USA. He has 40 publications to his credit so far.  

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