Dormant threat: Abnormal proteins unleash latent toxicity in neurodegenerative diseases

Thanks to modern medicine, humans tend to live much longer than before. Unfortunately, this also opens a wider window to develop chronic diseases with late onset, such as neurodegenerative diseases. Despite considerable research being devoted toward developing a cure for diseases like amyotrophic lateral sclerosis, there are currently no effective treatments.

Most of these neurological diseases have one thing in common: an accumulation of abnormal proteins around neurons. Researchers agree that these improperly fabricated proteins become progressively more toxic by interacting with healthy proteins, disrupting their functions. This picture, however, may be incomplete.

In a recent study published in the Journal of Cell Biology, scientists from Daegu Gyeongbuk Institute of Science and Technology, Korea, have discovered the mechanism of action by which abnormal proteins actually unleash the inherent, but normally latent, toxicity of a natural protein in neurons, causing defects in dendrites (branched parts of a neuron that connect to the next neuron). Therefore, their results provide some clarity as to what actually goes on in diseased neurons. Though the researchers focused on Machado-Joseph disease (MJD), the implications of their results are relevant to other diseases as well.

First, they screened existing data to find candidate genes that were abnormally expressed in MJD patients and mice models. Then, based on the results and using MJD flies as animal models, they identified a problematic transcription factor--a protein that controls and regulates the transcription from DNA of other proteins--called NF-κB. Though this transcription factor is essential for the proper functioning and development of dendrites, the researchers found that something went awry with it when abnormal MJD proteins were around.

Through multiple subsequent experiments, they elucidated a long chain of inhibitory/promoting interactions between native proteins that, at a certain point, clashes with the accumulated abnormal proteins and cascades into a "deregulation" of NF-κB. In turn, this improper regulation unlocks the latent toxicity of NF-κB.

Professor Sung Bae Lee, who led the study, remarks: "Our results open-up a new avenue toward finding cures for neurodegenerative diseases by creating inhibition-based drugs that target improperly regulated latent toxic factors." Such new potential treatments would directly target the early stages of neuron damage, stopping neurological disorders right on their tracks.

This study lights a beacon of hope for many countries that are struggling to deal with the problems of an aging society. "Korea will become a super-aged society in the near future and establishing an appropriate social system to care for and treat people with neurodegenerative diseases is turning into an urgent social issue," comments Professor Lee. This might be the first step in a completely new road toward treating these chronic age-related diseases.

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Reference

Authors: Myeong Hoon Han1, Min Jee Kwon1, Byung Su Ko1, Do Young Hyeon2, Davin Lee1, Hyung-Jun Kim3, Daehee Hwang2, and Sung Bae Lee1,4,5*
Title of original paper: NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases
Journal: Journal of Cell Biology
DOI: 10.1083/jcb.202004107

Affiliations: 1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology
2School of Biological Science, Seoul National University
3Dementia Research Group, Korea Brain Research Institute
4Protein Dynamics-Based Proteotoxicity Control Laboratory, Basic Research Lab, Daegu Gyeongbuk Institute of Science and Technology
5Well Aging Research Center, Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology

*Corresponding author's email: sblee@dgist.ac.kr

About Daegu Gyeongbuk Institute of Science and Technology (DGIST)

Daegu Gyeongbuk Institute of Science and Technology (DGIST) is a well-known and respected research institute located in Daegu, Republic of Korea. Established in 2004 by the Korean Government, the main aim of DGIST is to promote national science and technology, as well as to boost the local economy.

With a vision of "Changing the world through convergence", DGIST has undertaken a wide range of research in various fields of science and technology. DGIST has embraced a multidisciplinary approach to research and undertaken intensive studies in some of today's most vital fields. DGIST also has state-of-the-art-infrastructure to enable cutting-edge research in materials science, robotics, cognitive sciences, and communication engineering.

Website: https://www.dgist.ac.kr/en/html/sub01/010204.html

About the authors

Dr Sung Bae Lee, the principal investigator of this study, has been studying the pathogenic mechanisms of neurodegenerative diseases using Drosophila as a primary disease model system for about 20 years. Dr Lee has published over 50 papers in many high-impact journals, such as Nature, PNAS, and Cell Reports. In addition, Dr Min Jee Kwon, one of the co-first authors, is now studying at Harvard Medical School as a post-doc. Two other co-first authors, Myeong Hoon Han and Byung Su Ko, are graduate students of the Deptartment of Brain and Cognitive Sciences at DGIST. These three co-first authors are also actively studying the pathogenic mechanisms of neurodegenerative diseases.

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