Novel Small Protein Offers a Deeper Look at the Pathology of Alzheimer’s Disease
Update 22.12.2022
The protein, a variant of a well-known transcription 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.
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 transcription 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. Jee‑Yun 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 |
Jee‑Yun Park,
Hee‑Young
Sohn, Young Ho Koh & Chulman Jo |
Title of
original paper |
A splicing
variant of TFEB negatively regulates the TFEB‑autophagy
pathway |
Journal |
Scientific Reports |
DOI |
|
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
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/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.