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A Mechanism Underlying Most Common Cause of Epileptic Seizures Revealed
An interdisciplinary study shows that neurons carrying somatic mutations in MTOR can lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons
During fetal development, cells should migrate to the outer edge of the brain to form critical connections for information transfer and regulation in the body. When even a few cells fail to move to the correct location, the neurons become disorganized and this results in focal cortical dysplasia. This condition is the most common cause of seizures that cannot be controlled with medication in children and the second most common cause in adults.
Now, an interdisciplinary team studying neurogenetics, neural networks, and neurophysiology at KAIST has revealed how dysfunctions in even a small percentage of cells can cause disorder across the entire brain. They published their results on June 28 in Annals of Neurology.
The work builds on a previous finding, also by a KAIST scientists, who found that focal cortical dysplasia was caused by mutations in the cells involved in mTOR, a pathway that regulates signaling between neurons in the brain.
“Only 1 to 2% of neurons carrying mutations in the mTOR signaling pathway that regulates cell signaling in the brain have been found to include seizures in animal models of focal cortical dysplasia,” said Professor Jong-Woo Sohn from the Department of Biological Sciences. “The main challenge of this study was to explain how nearby non-mutated neurons are hyperexcitable.”
Initially, the researchers hypothesized that the mutated cells affected the number of excitatory and inhibitory synapses in all neurons, mutated or not. These neural gates can trigger or halt activity, respectively, in other neurons. Seizures are a result of extreme activity, called hyperexcitability. If the mutated cells upend the balance and result in more excitatory cells, the researchers thought, it made sense that the cells would be more susceptible to hyperexcitability and, as a result, seizures.
“Contrary to our expectations, the synaptic input balance was not changed in either the mutated or non-mutated neurons,” said Professor Jeong Ho Lee from the Graduate School of Medical Science and Engineering. “We turned our attention to a protein overproduced by mutated neurons.”
The protein is adenosine kinase, which lowers the concentration of adenosine. This naturally occurring compound is an anticonvulsant and works to relax vessels. In mice engineered to have focal cortical dysplasia, the researchers injected adenosine to replace the levels lowered by the protein. It worked and the neurons became less excitable.
“We demonstrated that augmentation of adenosine signaling could attenuate the excitability of non-mutated neurons,” said Professor Se-Bum Paik from the Department of Bio and Brain Engineering.
The effect on the non-mutated neurons was the surprising part, according to Paik. “The seizure-triggering hyperexcitability originated not in the mutation-carrying neurons, but instead in the nearby non-mutated neurons,” he said.
The mutated neurons excreted more adenosine kinase, reducing the adenosine levels in the local environment of all the cells. With less adenosine, the non-mutated neurons became hyperexcitable, leading to seizures.
“While we need further investigate into the relationship between the concentration of adenosine and the increased excitation of nearby neurons, our results support the medical use of drugs to activate adenosine signaling as a possible treatment pathway for focal cortical dysplasia,” Professor Lee said.
The Suh Kyungbae Foundation, the Korea Health Technology Research and Development Project, the Ministry of Health & Welfare, and the National Research Foundation in Korea funded this work.
-Publication:Koh, H.Y., Jang, J., Ju, S.H., Kim, R., Cho, G.-B., Kim, D.S., Sohn, J.-W., Paik, S.-B. and Lee, J.H. (2021), ‘Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia’ Annals of Neurology, 90: 285 299. (https://doi.org/10.1002/ana.26149)
-ProfileProfessor Jeong Ho Lee Translational Neurogenetics Labhttps://tnl.kaist.ac.kr/ Graduate School of Medical Science and Engineering KAIST
Professor Se-Bum Paik Visual System and Neural Network Laboratory http://vs.kaist.ac.kr/ Department of Bio and Brain EngineeringKAIST
Professor Jong-Woo Sohn Laboratory for Neurophysiology, https://sites.google.com/site/sohnlab2014/home Department of Biological SciencesKAIST
Dr. Hyun Yong Koh Translational Neurogenetics LabGraduate School of Medical Science and EngineeringKAIST
Dr. Jaeson Jang Ph.D.Visual System and Neural Network LaboratoryDepartment of Bio and Brain Engineering KAIST
Sang Hyeon Ju M.D.Laboratory for NeurophysiologyDepartment of Biological SciencesKAIST
2021.08.26 View 13957 -
Brain-Inspired Highly Scalable Neuromorphic Hardware Presented
Neurons and synapses based on single transistor can dramatically reduce the hardware cost and accelerate the commercialization of neuromorphic hardware
KAIST researchers fabricated a brain-inspired highly scalable neuromorphic hardware by co-integrating single transistor neurons and synapses. Using standard silicon complementary metal-oxide-semiconductor (CMOS) technology, the neuromorphic hardware is expected to reduce chip cost and simplify fabrication procedures.
The research team led by Yang-Kyu Choi and Sung-Yool Choi produced a neurons and synapses based on single transistor for highly scalable neuromorphic hardware and showed the ability to recognize text and face images. This research was featured in Science Advances on August 4.
Neuromorphic hardware has attracted a great deal of attention because of its artificial intelligence functions, but consuming ultra-low power of less than 20 watts by mimicking the human brain. To make neuromorphic hardware work, a neuron that generates a spike when integrating a certain signal, and a synapse remembering the connection between two neurons are necessary, just like the biological brain. However, since neurons and synapses constructed on digital or analog circuits occupy a large space, there is a limit in terms of hardware efficiency and costs. Since the human brain consists of about 1011 neurons and 1014 synapses, it is necessary to improve the hardware cost in order to apply it to mobile and IoT devices.
To solve the problem, the research team mimicked the behavior of biological neurons and synapses with a single transistor, and co-integrated them onto an 8-inch wafer. The manufactured neuromorphic transistors have the same structure as the transistors for memory and logic that are currently mass-produced. In addition, the neuromorphic transistors proved for the first time that they can be implemented with a ‘Janus structure’ that functions as both neuron and synapse, just like coins have heads and tails.
Professor Yang-Kyu Choi said that this work can dramatically reduce the hardware cost by replacing the neurons and synapses that were based on complex digital and analog circuits with a single transistor. "We have demonstrated that neurons and synapses can be implemented using a single transistor," said Joon-Kyu Han, the first author. "By co-integrating single transistor neurons and synapses on the same wafer using a standard CMOS process, the hardware cost of the neuromorphic hardware has been improved, which will accelerate the commercialization of neuromorphic hardware,” Han added.This research was supported by the National Research Foundation (NRF) and IC Design Education Center (IDEC).
-PublicationJoon-Kyu Han, Sung-Yool Choi, Yang-Kyu Choi, et al.“Cointegration of single-transistor neurons and synapses by nanoscale CMOS fabrication for highly scalable neuromorphic hardware,” Science Advances (DOI: 10.1126/sciadv.abg8836)
-ProfileProfessor Yang-Kyu ChoiNano-Oriented Bio-Electronics Labhttps://sites.google.com/view/nobelab/
School of Electrical EngineeringKAIST
Professor Sung-Yool ChoiMolecular and Nano Device Laboratoryhttps://www.mndl.kaist.ac.kr/
School of Electrical EngineeringKAIST
2021.08.05 View 11694 -
Prof. Changho Suh Named the 2021 James L. Massey Awardee
Professor Changho Suh from the School of Electrical Engineering was named the recipient of the 2021 James L.Massey Award. The award recognizes outstanding achievement in research and teaching by young scholars in the information theory community. The award is named in honor of James L. Massey, who was an internationally acclaimed pioneer in digital communications and revered teacher and mentor to communications engineers.
Professor Suh is a recipient of numerous awards, including the 2021 James L. Massey Research & Teaching Award for Young Scholars from the IEEE Information Theory Society, the 2019 AFOSR Grant, the 2019 Google Education Grant, the 2018 IEIE/IEEE Joint Award, the 2015 IEIE Haedong Young Engineer Award, the 2013 IEEE Communications Society Stephen O. Rice Prize, the 2011 David J. Sakrison Memorial Prize (the best dissertation award in UC Berkeley EECS), the 2009 IEEE ISIT Best Student Paper Award, the 2020 LINKGENESIS Best Teacher Award (the campus-wide Grand Prize in Teaching), and the four Departmental Teaching Awards (2013, 2019, 2020, 2021).
Dr. Suh is an IEEE Information Theory Society Distinguished Lecturer, the General Chair of the Inaugural IEEE East Asian School of Information Theory, and a Member of the Young Korean Academy of Science and Technology. He is also an Associate Editor of Machine Learning for the IEEE Transactions on Information Theory, the Editor for the IEEE Information Theory Newsletter, a Column Editor for IEEE BITS the Information Theory Magazine, an Area Chair of NeurIPS 2021, and on the Senior Program Committee of IJCAI 2019–2021.
2021.07.27 View 8865 -
Professor Kang’s Team Receives the IEEE Jack Newbauer Memorial Award
Professor Joonhyuk Kang of the School of Electrical Engineering received the IEEE Vehicular Technology Society’s 2021 Jack Neubauer Memorial Award for his team’s paper published in IEEE Transactions on Vehicular Technology. The Jack Neubauer Memorial Award recognizes the best paper published in the IEEE Transactions on Vehicular Technology journal in the last five years.
The team of authors, Professor Kang, Professor Sung-Ah Chung at Kyungpook National University, and Professor Osvaldo Simeone of King's College London reported their research titled Mobile Edge Computing via a UAV-Mounted Cloudlet: Optimization of Bit Allocation and Path Planning in IEEE Transactions on Vehicular Technology, Vol. 67, No. 3, pp. 2049-2063, in March 2018.
Their paper shows how the trajectory of aircraft is optimized and resources are allocated when unmanned aerial vehicles perform edge computing to help mobile device calculations. This paper has currently recorded nearly 400 citations (based on Google Scholar). "We are very happy to see the results of proposing edge computing using unmanned aerial vehicles by applying optimization theory, and conducting research on trajectory and resource utilization of unmanned aerial vehicles that minimize power consumption," said Professor Kang.
2021.07.12 View 8568 -
Prof. Sang Wan Lee Selected for 2021 IBM Academic Award
Professor Sang Wan Lee from the Department of Bio and Brain Engineering was selected as the recipient of the 2021 IBM Global University Program Academic Award. The award recognizes individual faculty members whose emerging science and technology contains significant interest for universities and IBM.
Professor Lee, whose research focuses on artificial intelligence and computational neuroscience, won the award for his research proposal titled A Neuroscience-Inspired Approach for Metacognitive Reinforcement Learning. IBM provides a gift of $40,000 to the recipient’s institution in recognition of the selection of the project but not as a contract for services.
Professor Lee’s project aims to exploit the unique characteristics of human reinforcement learning. Specifically, he plans to examines the hypothesis that metacognition, a human’s ability to estimate their uncertainty level, serves to guide sample-efficient and near-optimal exploration, making it possible to achieve an optimal balance between model-based and model-free reinforcement learning.
He was also selected as the winner of the Google Research Award in 2016 and has been working with DeepMind and University College London to conduct basic research on decision-making brain science to establish a theory on frontal lobe meta-enhance learning.
"We plan to conduct joint research for utilizing brain-based artificial intelligence technology and frontal lobe meta-enhanced learning technology modeling in collaboration with an international research team including IBM, DeepMind, MIT, and Oxford,” Professor Lee said.
2021.06.25 View 12926 -
Biomimetic Resonant Acoustic Sensor Detecting Far-Distant Voices Accurately to Hit the Market
A KAIST research team led by Professor Keon Jae Lee from the Department of Materials Science and Engineering has developed a bioinspired flexible piezoelectric acoustic sensor with multi-resonant ultrathin piezoelectric membrane mimicking the basilar membrane of the human cochlea. The flexible acoustic sensor has been miniaturized for embedding into smartphones and the first commercial prototype is ready for accurate and far-distant voice detection.
In 2018, Professor Lee presented the first concept of a flexible piezoelectric acoustic sensor, inspired by the fact that humans can accurately detect far-distant voices using a multi-resonant trapezoidal membrane with 20,000 hair cells. However, previous acoustic sensors could not be integrated into commercial products like smartphones and AI speakers due to their large device size.
In this work, the research team fabricated a mobile-sized acoustic sensor by adopting ultrathin piezoelectric membranes with high sensitivity. Simulation studies proved that the ultrathin polymer underneath inorganic piezoelectric thin film can broaden the resonant bandwidth to cover the entire voice frequency range using seven channels. Based on this theory, the research team successfully demonstrated the miniaturized acoustic sensor mounted in commercial smartphones and AI speakers for machine learning-based biometric authentication and voice processing. (Please refer to the explanatory movie KAIST Flexible Piezoelectric Mobile Acoustic Sensor).
The resonant mobile acoustic sensor has superior sensitivity and multi-channel signals compared to conventional condenser microphones with a single channel, and it has shown highly accurate and far-distant speaker identification with a small amount of voice training data. The error rate of speaker identification was significantly reduced by 56% (with 150 training datasets) and 75% (with 2,800 training datasets) compared to that of a MEMS condenser device.
Professor Lee said, “Recently, Google has been targeting the ‘Wolverine Project’ on far-distant voice separation from multi-users for next-generation AI user interfaces. I expect that our multi-channel resonant acoustic sensor with abundant voice information is the best fit for this application. Currently, the mass production process is on the verge of completion, so we hope that this will be used in our daily lives very soon.”
Professor Lee also established a startup company called Fronics Inc., located both in Korea and U.S. (branch office) to commercialize this flexible acoustic sensor and is seeking collaborations with global AI companies.
These research results entitled “Biomimetic and Flexible Piezoelectric Mobile Acoustic Sensors with Multi-Resonant Ultrathin Structures for Machine Learning Biometrics” were published in Science Advances in 2021 (7, eabe5683).
-Publication
“Biomimetic and flexible piezoelectric mobile acoustic sensors with multiresonant ultrathin structures for machine learning biometrics,” Science Advances (DOI: 10.1126/sciadv.abe5683)
-Profile
Professor Keon Jae Lee
Department of Materials Science and Engineering
Flexible and Nanobio Device Lab
http://fand.kaist.ac.kr/
KAIST
2021.06.14 View 10618 -
KAIST Listed as Top 100 Global Innovator by Clarivate
KAIST was named as one of the Top 100 Global Innovators 2021 by Clarivate. Among the top 100, 42 US corporations, including Amazon, Apple, Google, and Facebook, and 29 Japanese corporations made the list. The list included four Korean corporations Samsung Electronics, LG Electronics, LS Electronics, and SK Telecommunications. KAIST, the only university listed as a global innovator, regained its place in the Top 100 Global Innovators this year after last being named in 2013. Industrywide, the electronics and semiconductor sectors took the majority of the top global innovators spots with 21 and 12 corporations respectively.
President Kwang Hyung Lee received the trophy from Clarivate Korea Regional Director Seongsik Ahn on May 12 at KAIST’s main campus. President Lee said, “We are glad that our continued innovation efforts are receiving worldwide recognition and will continue to strive for sustainable growth as a university that creates global value and impact.”
Every year since 2012, the Top 100 Global Innovators has identified companies and institutions at the pinnacle of the global innovation landscape by measuring the ideation culture that produces patents and puts them at the forefront. Clarivate tracks innovation based on four factors: 1. volume of patents 2. influence 3. Success and 4. globalization using patents, patents indices, and citation index solutions.
For measuring the patent volume, the Top 100 candidate must meet a threshold of 100 granted patents received in the past five years and more than 500 in the Derwent World Patents Index over any time period. Clarivate assesses the level of influence of the patented ideas by reviewing the number of external citations their inventions received over the past five years. For measuring success, they look at how successful each candidate has been getting their applications for patent protection approved by patent offices around the world over past five years. Globalization measures the investment levels of each candidate in their patent applications, a metric designed to assess both the importance of invention to the companies as well as the footprint of commercialization.
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2021.05.12 View 5825 -
Dongwon Chairman Donates ₩50 Billion to Fund AI Graduate School
Dongwon Group Honorary Chairman and Founder Jae-chul Kim donated his private property worth ₩50 billion (US $46 million) to KAIST on December 16. Honorary Chairman Kim’s gift will fund the KAIST Graduate School of AI (GSAI), which was established last year. The KAIST GSAI will be re-named the ‘Kim Jae-chul Graduate School of AI’ to honor Honorary Chairman Kim.
This is the third major donation that KAIST has received this year following KAIST Development Foundation Chairman Soo-Young Lee’s ₩67.6 billion in real estate in July and another ₩10 billion from a KAIST alumnus, Chairman Byeong-Gyu Chang of Krafton, in January.
“KAIST, as the cradle that trains Korea’s best talents in science and technology, has been at the forefront of leading national development over the past 50 years. I hope that KAIST will also strive to nurture global talents who excel in AI innovation and steer Korea’s new advancements to lead the Fourth Industrial Revolution,” said Honorary Chairman Kim during the donation ceremony at KAIST’s main campus in Daejeon.
The ceremony was held in strict compliance with Level Two social distancing guidelines and measures in response to the persistent coronavirus. Less than 50 people, including Honorary Chairman Kim’s family, President Sung-Chul Shin, and professors from key posts at KAIST, attended the ceremony.
Dongwon Group is one of the leading fishery companies in Korea, established in 1969 by Honorary Chairman Kim. He recalled memories of his childhood as he explained the background of the donation, saying, “When I was young, I searched for Korea’s future in the world’s oceans. However, a new future lies in the ‘oceans of data.’”
“I have been pondering how I could further contribute to my country, and realized that bringing up talented individuals in the AI and data science-related fields is important. I hope that my donation today will aid the take-off of KAIST’s great voyage towards becoming a global “flagship” in the new eras to come,” Honorary Chairman Kim added.
To this, President Shin responded acclaiming the noblesse oblige held by Honorary Chairman Kim to further develop Korea’s science and technology and make Korea into a leader in AI innovation.
“We will always keep KAIST’s role and mission close to our hearts and do our best to make KAIST into a global hub for talent cultivation and R&D in AI, based on Honorary Chairman Kim’s donation,” said President Shin.
With Honorary Chairman Kim’s donation, the KAIST GSAI will first expand its faculty in both quantity and quality. By expanding the number of full-time, highly qualified professors to 40 by 2030, the School will train the most talented personnel in fusion and convergence AI.
The KAIST GSAI opened in August 2019 as the first school in Korea to be selected as part of the ‘2019 Graduate School for AI Support Project’ by the Ministry of Science and ICT. The current faculty is composed of 13 full-time professors including ex-researchers from AI labs of global conglomerates including Google, IBM Watson, and Microsoft, as well as eight adjunct professors, making a total of 21 faculty members. There are currently 138 students attending the School, including 79 master’s students, 17 in the integrated MS-PhD program, and 42 PhD candidates.
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2020.12.16 View 9503 -
KAIST and Google Partner to Develop AI Curriculum
Two KAIST professors, Hyun Wook Ka from the School of Transdisciplinary Studies and Young Jae Jang from the Department of Industrial and Systems Engineering, were recipients of Google Education Grants that will support the development of new AI courses integrating the latest industrial technology. This collaboration is part of the KAIST-Google Partnership, which was established in July 2019 with the goal of nurturing AI talent at KAIST.
The two proposals -- Professor Ka’s ‘Cloud AI-Empowered Multimodal Data Analysis for Human Affect Detection and Recognition’ and Professor Jang’s ‘Learning Smart Factory with AI’-- were selected by the KAIST Graduate School of AI through a school-wide competition held in July. The proposals then went through a final review by Google and were accepted. The two professors will receive $7,500 each for developing AI courses using Google technology for one year.
Professor Ka’s curriculum aims to provide a rich learning experience for students by providing basic knowledge on data science and AI and helping them obtain better problem solving and application skills using practical and interdisciplinary data science and AI technology.
Professor Jang’s curriculum is designed to solve real-world manufacturing problems using AI and it will be field-oriented. Professor Jang has been managing three industry-academic collaboration centers in manufacturing and smart factories within KAIST and plans to develop his courses to go beyond theory and be centered on case studies for solving real-world manufacturing problems using AI.
Professor Jang said, “Data is at the core of smart factories and AI education, but there is often not enough of it for the education to be effective. The KAIST Advanced Manufacturing Laboratory has a testbed for directly acquiring data generated from real semiconductor automation equipment, analyzing it, and applying algorithms, which enables truly effective smart factory and AI education.”
KAIST signed a partnership with Google in July 2019 to foster global AI talent and is operating various programs to train AI experts and support excellent AI research for two years.
The Google AI Focused Research Award supports world-class faculty performing cutting-edge research and was previously awarded to professors Sung Ju Hwang from the Graduate School of AI and Steven Whang from the School of Electrical Engineering along with Google Cloud Platform (GCP) credits. These two professors have been collaborating with Google teams since October 2018 and recently extended their projects to continue through 2021.
In addition, a Google Ph.D. Fellowship was awarded to Taesik Gong from the School of Computing in October this year, and three Student Travel Grants were awarded to Sejun Park from the School of Electrical Engineering, Chulhyung Lee from the Department of Mathematical Sciences, and Sangyun Lee from the School of Computing earlier in March. Five students were also recommended for the Google Internship program in March.
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2020.12.11 View 13247 -
Taesik Gong Named Google PhD Fellow
PhD candidate Taesik Gong from the School of Computing was named a 2020 Google PhD Fellow in the field of machine learning.
The Google PhD Fellowship Program has recognized and supported outstanding graduate students in computer science and related fields since 2009. Gong is one of two Korean students chosen as the recipients of Google Fellowships this year. A total of 53 students across the world in 12 fields were awarded this fellowship.
Gong’s research on condition-independent mobile sensing powered by machine learning earned him this year’s fellowship. He has published and presented his work through many conferences including ACM SenSys and ACM UbiComp, and has worked at Microsoft Research Asia and Nokia Bell Labs as a research intern. Gong was also the winner of the NAVER PhD Fellowship Award in 2018.
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2020.10.15 View 12431 -
Tinkering with Roundworm Proteins Offers Hope for Anti-aging Drugs
- The somatic nuclear protein kinase VRK-1 increases the worm’s lifespan through AMPK activation, and this mechanism can be applied to promoting human longevity, the study reveals. -
KAIST researchers have been able to dial up and down creatures’ lifespans by altering the activity of proteins found in roundworm cells that tell them to convert sugar into energy when their cellular energy is running low. Humans also have these proteins, offering up the intriguing possibilities for developing longevity-promoting drugs. These new findings were published on July 1 in Science Advances.
The roundworm Caenorhabditis elegans (C. elegans), a millimeter-long nematode commonly used in lab testing, enjoyed a boost in its lifespan when researchers tinkered with a couple of proteins involved in monitoring the energy use by its cells.
The proteins VRK-1 and AMPK work in tandem in roundworm cells, with the former telling the latter to get to work by sticking a phosphate molecule, composed of one phosphorus and four oxygen atoms, on it. In turn, AMPK’s role is to monitor energy levels in cells, when cellular energy is running low. In essence, VRK-1 regulates AMPK, and AMPK regulates the cellular energy status.
Using a range of different biological research tools, including introducing foreign genes into the worm, a group of researchers led by Professor Seung-Jae V. Lee from the Department of Biological Sciences at KAIST were able to dial up and down the activity of the gene that tells cells to produce the VRK-1 protein. This gene has remained pretty much unchanged throughout evolution. Most complex organisms have this same gene, including humans.
Lead author of the study Sangsoon Park and his colleagues confirmed that the overexpression, or increased production, of the VRK-1 protein boosted the lifespan of the C. elegans, which normally lives just two to three weeks, and the inhibition of VRK-1 production reduced its lifespan.
The research team found that the activity of the VRK-1-to-AMPK cellular-energy monitoring process is increased in low cellular energy status by reduced mitochondrial respiration, the set of metabolic chemical reactions that make use of the oxygen the worm breathes to convert macronutrients from food into the energy “currency” that cells spend to do everything they need to do.
It is already known that mitochondria, the energy-producing engine rooms in cells, play a crucial role in aging, and declines in the functioning of mitochondria are associated with age-related diseases. At the same time, the mild inhibition of mitochondrial respiration has been shown to promote longevity in a range of species, including flies and mammals.
When the research team performed similar tinkering with cultured human cells, they found they could also replicate this ramping up and down of the VRK-1-to-AMPK process that occurs in roundworms.
“This raises the intriguing possibility that VRK-1 also functions as a factor in governing human longevity, and so perhaps we can start developing longevity-promoting drugs that alter the activity of VRK-1,” explained Professor Lee.
At the very least, the research points us in an interesting direction for investigating new therapeutic strategies to combat metabolic disorders by targeting the modulation of VRK-1. Metabolic disorders involve the disruption of chemical reactions in the body, including diseases of the mitochondria.
But before metabolic disorder therapeutics or longevity drugs can be contemplated by scientists, further research still needs to be carried out to better understand how VRK-1 works to activate AMPK, as well as figure out the precise mechanics of how AMPK controls cellular energy.
This work was supported by the National Research Foundation (NRF), and the Ministry of Science and ICT (MSIT) of Korea.
Image credit: Seung-Jae V. LEE, KAIST.
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of news coverage of this paper only.
Publication:
Park, S., et al. (2020) ‘VRK-1 extends life span by activation of AMPK via phosphorylation’. Science Advances, Volume 6. No. 27, eaaw7824. Available online at https://doi.org/10.1126/sciadv.aaw7824
Profile: Seung-Jae V. Lee, Ph.D.
Professor
seungjaevlee@kaist.ac.kr
https://sites.google.com/view/mgakaist
Molecular Genetics of Aging Laboratory
Department of Biological Sciences
Korea Advanced Institute of Science and Technology (KAIST)
https://www.kaist.ac.krDaejeon 34141, Korea
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2020.07.31 View 12915 -
Simple Molecular Reagents to Treat Alzheimer’s Disease
- Researchers report minimalistic principles for designing small molecules with multiple reactivities against dementia. -
Sometimes the most complex problems actually have very simple solutions. A group of South Korean researchers reported an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents against neurodegenerative disorders. The team developed redox-active aromatic molecular reagents with a simple structural composition that can simultaneously target and modulate various pathogenic factors in complex neurodegenerative disorders such as Alzheimer’s disease.
Alzheimer’s disease is one of the most prevalent neurodegenerative disorders, affecting one in ten people over the age of 65. Early-onset dementia also increasingly affects younger people.
A number of pathogenic elements such as reactive oxygen species, amyloid-beta, and metal ions have been suggested as potential causes of Alzheimer’s disease. Each element itself can lead to Alzheimer’s disease, but interactions between them may also aggravate the patient’s condition or interfere with the appropriate clinical care.
For example, when interacting with amyloid-beta, metal ions foster the aggregation and accumulation of amyloid-beta peptides that can induce oxidative stress and toxicity in the brain and lead to neurodegeneration.
Because these pathogenic factors of Alzheimer’s disease are intertwined, developing therapeutic agents that are capable of simultaneously regulating metal ion dyshomeostasis, amyloid-beta agglutination, and oxidative stress responses remains a key to halting the progression of the disease.
A research team led by Professor Mi Hee Lim from the Department of Chemistry at KAIST demonstrated the feasibility of structure-mechanism-based molecular design for controlling a molecule’s chemical reactivity toward the various pathological factors of Alzheimer’s disease by tuning the redox properties of the molecule.
This study, featured as the ‘ACS Editors’ Choice’ in the May 6th issue of the Journal of the American Chemical Society (JACS), was conducted in conjunction with KAIST Professor Mu-Hyun Baik’s group and Professor Joo-Young Lee’s group at the Asan Medical Center.
Professor Lim and her collaborators rationally designed and generated 10 compact aromatic molecules presenting a range of redox potentials by adjusting the electronic distribution of the phenyl, phenylene, or pyridyl moiety to impart redox-dependent reactivities against the multiple pathogenic factors in Alzheimer’s disease.
During the team’s biochemical and biophysical studies, these designed molecular reagents displayed redox-dependent reactivities against numerous desirable targets that are associated with Alzheimer’s disease such as free radicals, metal-free amyloid-beta, and metal-bound amyloid-beta.
Further mechanistic results revealed that the redox properties of these designed molecular reagents were essential for their function. The team demonstrated that these reagents engaged in oxidative reactions with metal-free and metal-bound amyloid-beta and led to chemical modifications. The products of such oxidative transformations were observed to form covalent adducts with amyloid-beta and alter its aggregation.
Moreover, the administration of the most promising candidate molecule significantly attenuated the amyloid pathology in the brains of Alzheimer’s disease transgenic mice and improved their cognitive defects.
Professor Lim said, “This strategy is straightforward, time-saving, and cost-effective, and its effect is significant. We are excited to help enable the advancement of new therapeutic agents for neurodegenerative disorders, which can improve the lives of so many patients.”
This work was supported by the National Research Foundation (NRF) of Korea, the Institute for Basic Science (IBS), and the Asan Institute for Life Sciences.
Image credit: Professor Mi Hee Lim, KAIST
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of the news coverage of this paper only.
Publication:
Kim, M. et al. (2020) ‘Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.’ Journal of the American Chemical Society (JACS), Volume 142, Issue 18, pp.8183-8193. Available online at https://doi.org/10.1021/jacs.9b13100
Profile:
Mi Hee Lim
Professor
miheelim@kaist.ac.kr
http://sites.google.com/site/miheelimlab
Lim Laboratory
Department of Chemistry
KAIST
Profile:
Mu-Hyun Baik
Professor
mbaik2805@kaist.ac.kr
https://baik-laboratory.com/
Baik Laboratory
Department of Chemistry
KAIST
Profile:
Joo-Yong Lee
Professor
jlee@amc.seoul.kr
Asan Institute for Life Sciences
Asan Medical Center
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2020.05.11 View 16595