Cell
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Two Professors Recognized for the National R&D Excellence 100
< Professor Haeng-Ki Lee (left) and Professor Jeong-Ho Lee (right) >
Two KAIST professors were listed among the 2019 National R&D Excellence 100 announced by the Ministry of Science and ICT and the Korea Institute of S&T Evaluation and Planning.
Professor Haeng-Ki Lee from the Department of Civil and Environmental Engineering was recognized in the field of mechanics and materials for his research on developing new construction materials through the convergence of nano- and biotechnologies.
In the field of life and marine science, Professor Jeong-Ho Lee from the Graduate School of Medical Science and Engineering was lauded for his research of diagnostic tools and therapies for glioblastoma and pediatric brain tumors.
A certificate from the Minister of Ministry of Science and ICT will be conferred to these two professors, and their names will be inscribed on a special 2019 National R&D Excellence 100 plaque to celebrate their achievements. The professors will also be given privileges during the process of new R&D project selection.
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2019.10.15 View 9376 -
Researchers Describe a Mechanism Inducing Self-Killing of Cancer Cells
(Professor Kim (left) and lead author Lee)
Researchers have described a new mechanism which induces the self-killing of cancer cells by perturbing ion homeostasis. A research team from the Department of Biochemical Engineering has developed helical polypeptide potassium ionophores that lead to the onset of programmed cell death. The ionophores increase the active oxygen concentration to stress endoplasmic reticulum to the point of cellular death.
The electrochemical gradient between extracellular and intracellular conditions plays an important role in cell growth and metabolism. When a cell’s ion homeostasis is disturbed, critical functions accelerating the activation of apoptosis are inhibited in the cell.
Although ionophores have been intensively used as an ion homeostasis disturber, the mechanisms of cell death have been unclear and the bio-applicability has been limited. In the study featured at Advanced Science, the team presented an alpha helical peptide-based anticancer agent that is capable of transporting potassium ions with water solubility. The cationic, hydrophilic, and potassium ionic groups were combined at the end of the peptide side chain to provide both ion transport and hydrophilic properties.
These peptide-based ionophores reduce the intracellular potassium concentration and at the same time increase the intracellular calcium concentration. Increased intracellular calcium concentrations produce intracellular reactive oxygen species, causing endoplasmic reticulum stress, and ultimately leading to apoptosis.
Anticancer effects were evaluated using tumor-bearing mice to confirm the therapeutic effect, even in animal models. It was found that tumor growth was strongly inhibited by endoplasmic stress-mediated apoptosis.
Lead author Dr. Dae-Yong Lee said, “A peptide-based ionophore is more effective than conventional chemotherapeutic agents because it induces apoptosis via elevated reactive oxygen species levels. Professor Yeu-Chun Kim said he expects this new mechanism to be widely used as a new chemotherapeutic strategy. This research was funded by the National Research Foundation.
2019.08.28 View 18078 -
Autophagy in Dendritic Cells Helps Anticancer Activity
Autophagy contributes to the homeostasis of a cell and recently another function of autophagy has been reported. A KAIST research team found that the autophagy of dendritic cells supports T-cell anticancer activity.
Autophagy is a process of maintaining cell homeostasis by removing cellular waste and damaged cellular organelles; nevertheless, its role in the presentation of phagocytized tumor-associated antigens remains vague.
Meanwhile, dendritic cells are the ones that recognize pathogens or cancer antigens, and induce immune responses in T cells. When cancer cells are killed by radiation or an anticancer drug, dendritic cells absorb and remove them and present antigens on their surface to transfer them to T-cells.
Professor Heung Kyu Lee from the Graduate School of Medical Science and Engineering and his team found that the autophagy of dendritic cells plays a key role in T-cell activation and they proposed the principles of enhancing anti-cancer effects.
Their experiments showed that T-cell activation of dendritic cells as well as anticancer immune response dropped when there is a deficiency of Atg5 (autophagy-related) in dendritic cells.
Interestingly, Atg5-deficient dendritic cells significantly elevated receptor CD36 on the surface of the cells, which increased the phagocytosis of apoptotic tumor cells yet restricted the activation of T-cells.
At this time, when introducing antibodies into the system in order to block the receptor CD36, the anti-tumor T-cell response increased substantially while tumor growth declined.
Professor Lee said, “This study allowed us to explore the role of autophagy in the anti-cancer immune response of T-cells. We look forward to developing targeted anti-cancer therapies using the receptor CD36.”
This research was published in Autophagy (10.1080/15548627.2019.1596493) on March 22, 2019.
Figure 1.Mechanism of autophagy in dendritic cells
Figure 2. A role of autophagy in dendritic cells
2019.05.13 View 49920 -
KAIST Unveils the Hidden Control Architecture of Brain Networks
(Professor Kwang-Hyun Cho and his team)
A KAIST research team identified the intrinsic control architecture of brain networks. The control properties will contribute to providing a fundamental basis for the exogenous control of brain networks and, therefore, has broad implications in cognitive and clinical neuroscience.
Although efficiency and robustness are often regarded as having a trade-off relationship, the human brain usually exhibits both attributes when it performs complex cognitive functions. Such optimality must be rooted in a specific coordinated control of interconnected brain regions, but the understanding of the intrinsic control architecture of brain networks is lacking.
Professor Kwang-Hyun Cho from the Department of Bio and Brain Engineering and his team investigated the intrinsic control architecture of brain networks. They employed an interdisciplinary approach that spans connectomics, neuroscience, control engineering, network science, and systems biology to examine the structural brain networks of various species and compared them with the control architecture of other biological networks, as well as man-made ones, such as social, infrastructural and technological networks.
In particular, the team reconstructed the structural brain networks of 100 healthy human adults by performing brain parcellation and tractography with structural and diffusion imaging data obtained from the Human Connectome Project database of the US National Institutes of Health.
The team developed a framework for analyzing the control architecture of brain networks based on the minimum dominating set (MDSet), which refers to a minimal subset of nodes (MD-nodes) that control the remaining nodes with a one-step direct interaction. MD-nodes play a crucial role in various complex networks including biomolecular networks, but they have not been investigated in brain networks.
By exploring and comparing the structural principles underlying the composition of MDSets of various complex networks, the team delineated their distinct control architectures. Interestingly, the team found that the proportion of MDSets in brain networks is remarkably small compared to those of other complex networks. This finding implies that brain networks may have been optimized for minimizing the cost required for controlling networks. Furthermore, the team found that the MDSets of brain networks are not solely determined by the degree of nodes, but rather strategically placed to form a particular control architecture.
Consequently, the team revealed the hidden control architecture of brain networks, namely, the distributed and overlapping control architecture that is distinct from other complex networks. The team found that such a particular control architecture brings about robustness against targeted attacks (i.e., preferential attacks on high-degree nodes) which might be a fundamental basis of robust brain functions against preferential damage of high-degree nodes (i.e., brain regions).
Moreover, the team found that the particular control architecture of brain networks also enables high efficiency in switching from one network state, defined by a set of node activities, to another – a capability that is crucial for traversing diverse cognitive states.
Professor Cho said, “This study is the first attempt to make a quantitative comparison between brain networks and other real-world complex networks. Understanding of intrinsic control architecture underlying brain networks may enable the development of optimal interventions for therapeutic purposes or cognitive enhancement.”
This research, led by Byeongwook Lee, Uiryong Kang and Hongjun Chang, was published in iScience (10.1016/j.isci.2019.02.017) on March 29, 2019.
Figure 1. Schematic of identification of control architecture of brain networks.
Figure 2. Identified control architectures of brain networks and other real-world complex networks.
2019.04.23 View 37451 -
Novel Strategies to Transform a Commercially Available Iboga Alkaloid to Post-Iboga Alkaloids
(PhD candidate HyeonggeunLim, Professor Sunkyu Han, PhD candidate Sikwang Seong)
KAIST chemists have synthesized seven different iboga and post-iboga natural products from commercially available catharanthine by mirroring nature’s biosynthetic post-modification of the iboga skeleton. They devised a novel strategy to biosynthesize the natural products via a series of selective and efficient oxidation and rearrangement reactions. This will serve as a stepping stone for developing therapeutic medications against cancer and narcotics addiction.
The research team, led by Professor Sunkyu Han, conceptualized and coined the term “Post-Iboga” alkaloids to describe the natural products that are biosynthetically derived from iboga-type alkaloids, which are composed of rearranged indole and/or isoquinuclidine backbones.
Iboga alkaloids have attracted significant attention from the scientific community due to their intriguing polycyclic structures and potential therapeutic uses against drug addictions. Nature has evolved to add architectural repertoires to this family of secondary metabolites by diversifying the iboga frameworks.
Notable examples are the FDA-approved anticancer drugs vinblastine and vincristine, both derived by the oxidative dimerization of catharanthine and vindoline subunits. Admittedly, synthetic foci toward the biosynthetic iboga-derivatives have historically been on these aforementioned dimeric natural products.
Recent natural product isolation studies on Tabernaemontana corymbosa and Ervatamia officinalis species have resulted in discoveries of various secondary metabolites that are biosynthetically derived from iboga alkaloids. These recent outbursts of iboga-derived natural product isolation reports have kindled interests toward these family of natural products.
The research team utilized (+)-catharanthine, the starting material for the industrial production of the anticancer drug Navelbine®. Well-orchestrated oxidations at the C19 position and the indole moiety of the catharanthine derivative, followed by differential rearrangements under acidic conditions, provided synthetic samples of voatinggine and tabertinggine respectively.
On the other hand, opportune oxidations at the C19 position and the alpha position of the tertiary amine moiety of the catharantine derivative, followed by a transhemiaminalization, produced the first synthetic sample of chippiine/dippinine-type natural product, dippinine B.
It is important to note that the chippiine and dippinine-type alkaloids have been targeted among synthetic chemists for over 30 years but had not succumbed to synthesis prior to this report.
Professor Han believes that their study will serve as a blueprint for further explorations of the synthesis, biosynthesis, and pharmacology of this emerging family of natural products. This study was published in Chem on November 15, 2018 (DOI: 10.1016/j.chempr.2018.10.009).
2018.11.16 View 4935 -
Dr. Sejeong Kim Recognized as Excellent Young Scientist
(Dr. Sejeong Kim)
Dr. Sejeong Kim, a postdoctoral research associate in the School of Mathematical and Physical Sciences at the University of Technology Sydney was honored to receive the Excellence Award for a Young Scientist by the Korea Federation of Women’s Science & Technology Association (KOFWST). The award ceremony will be held on October 31 in Seoul.
KOFWST recognizes ten promising young female scientists and engineers every year who show significant potential, passion, and remarkable achievement in their work. The awardees are selected among those who finished their degree within the previous five years. Dr. Kim earned her Ph.D. in physics at KAIST in 2014 and was selected as the winner in the field of physics in recognition of her outstanding research activities in photonics.
Dr. Kim conducted various research activities in the field of photonics and was published in high impact journals including Nano Letters and Advanced materials. In July, she developed the first photonic cavity from van der Waals materials and published the study in Nature Communications titled “Photonic Crystal Cavities from Hexagonal Boron Nitride.” At UTS, she carries out research activities supervised by Professor Igor Aharonovich and has engaged in many science outreach activities.
2018.10.18 View 4855 -
Mechanism Leading to Cortical Malformation from Brain-Only Mutations Identified
Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark.
A research team led by Professor Jeong Ho Lee in the Graduate School of Medical Science and Engineering at KAIST has recently investigated the molecular mechanism of defective neuronal migration in FMCDs. Their research results were published online in Neuron on June 21, 2018.
The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear.
To study the molecular mechanism of brain cortical dyslamination, the research team utilized patients’ brain tissues and modeled the MTOR mutation-carrying cell and animal models recapitulating the pathogenesis and symptoms of FMCD patients. By performing comprehensive molecular genetic experiments, they found that the formation of primary cilia, one of cellular organelles, was disrupted in MTOR mutation-carrying neurons and demonstrated that this ciliary disruption was a cause of cortical dyslamination in FMCDs.
MTOR mutations prevented degradation of the OFD1 protein, one of the negative regulators of ciliary formation. As a result, the OFD1 protein was abnormally accumulated in MTOR mutation-carrying neurons, causing focal cortical dyslamination. By suppressing the expression of the OFD1 protein, the research team was able to rescue the defective formation of primary cilia, leading to the restoration of cortical dyslamination and defective neuronal migration considerably.
Based on these results, the research team is carrying out further research to develop novel therapeutics for patients with FMCDs caused by brain-only mutations.
This work was supported by grants from the Suh Kyungbae Foundation and Citizens United for Research in Epilepsy.
The research paper is titled “Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination.” (Digital Object Identifier #: 10.1016/j.neuron.2018.05.039)
Picture 1: The disrupted formation of primary cilia in brain tissues of FMCD mouse models and patients with FMCDs caused by brain somatic mutations in MTOR.
Picture 2: The rescue of defective ciliary formation in FMCD mouse models leading to the restoration of cortical dyslamination and defective neuronal migration.
2018.07.02 View 7968 -
Lead-free, Efficient Perovskite for Photovoltaic Cells
(Clockwise from left: Post-doc Researcher Lamjed Debbichi, Master’s Candidate Songju Lee, Professor Min Seok Jang and Professor Hyungjun Kim)
A KAIST research team has proposed a perovskite material, Cs2Au2I6 that serves as a potential active material for highly efficient lead-free thin-film photovoltaic devices. This material is expected to lay the foundation to overcome previously known limitations of perovskite including its stability and toxicity issues.
As strong candidates for next-generation high-efficiency photovoltaic cells, perovskite photovoltaic cells have a maximum photoconversion efficiency of 22%, comparable to high-performance crystalline silicon photovoltaic cells. In addition, perovskite-based cells can be fabricated at low temperatures, thereby bringing about dramatic cost reductions.
However, it has been noted that conventional organic-inorganic hybrid perovskite materials exhibit low stability, eventually degrading their performance and making them unfit for continued use. Moreover, their inclusion of lead has undermined their environmental friendliness.
In light of this, a joint team led by Professor Hyungjun Kim from the KAIST Department of Chemistry and Professor Min Seok Jang from the School of Electrical Engineering has analyzed a previously discovered perovskite material, Cs2Au2I6, consisting of only inorganic substances and investigated its suitability for application in thin-film photovoltaic devices. Theoretical investigations suggests that this new perovskite material is not only as efficient but also more stable and environment friendly compared to the conventional perovskite materials. For this analysis, the team developed multiscale multiphysics simulation frameworks. Atomic-scale first-principle quantum calculations were carried out to study the optical properties of the proposed material, and device-scale electromagnetic simulations were conducted to suggest that the material could indeed serve as a promising photovoltaic substance at the device level.
From this point onward, the research team plans to extend the study in two directions: an empirical study to apply the perovskite material in real-world photovoltaic cells and a theoretical analysis to find the optimal and highly stable material for photovoltaic cells. The team said, “Perovskite materials are highly efficient, but in order to completely replace the conventional solar cells, their stability and toxicity issues must first be resolved.” They added that this research is expected to accelerate related studies in pursuit of high-efficiency, environment-friendly perovskite materials.
This research, led by post-doc researcher Lamjed Debbichi and master’s candidate Songju Lee, was selected as the front cover article of Advanced Materials on March 22.
Figure 1. Cover of Advanced Materials
Figure 2. Schematic of full solar cell device structure
2018.06.08 View 8283 -
Activation of Bystander Immune Cells during Acute Hepatitis A.
A KAIST research team has identified a process of tissue damage caused by bystander immune cells in acute viral infections. This research will pave the way for research to understand the principles of tissue damage in viral infections and immune diseases, and can point toward a possible therapeutic target for the treatment.
Upon viral infection, viral replication itself destroys human cells, but in some cases, viral replication is not the direct cause of the tissue damage. In particular, the destruction of infected cells is the primary cause of tissue damage during non-cytopathic viral infections such as hepatitis A virus, hepatitis B virus and hepatitis C virus. However, the underlying pathological mechanisms involved in the tissue damage during viral infections have not been fully elucidated.
Specificity is one of the most important characteristics of the immune system. In general, infection from a certain virus specifically activates immune cells targeting the virus, while other immune cells specific to different viruses remain inactive.
An immune cell not specific to an infected virus is called a bystander immune cell. A phenomenon that activates irrelevant immune cells not originally targeting the infecting virus, called the activation of bystander immune cells, is already known to the world; however, its clinical significance has not been investigated thoroughly.
Professor Eui-Cheol Shin and Professor Su-Hyung Park from the Graduate School of Medical Science and Engineering analyzed patients with acute hepatitis A, in collaboration with Chung-Ang University Hospital.
The team found not only immune cells specifically targeting the hepatitis A virus were activated, but also bystander immune cells were activated and involved in the damaging of liver tissues during acute hepatitis A.
According to the research, when a person is infected with hepatitis A virus, hepatitis A virus-infected cells produce IL-15, which induces the activation of bystander immune cells. Activated bystander immune cells exert innate-like cytotoxicity, triggered by activating receptors NKG2D and NKp30 and this can lead to liver injury.
Through describing the cause of excessive tissue damage during acute viral hepatitis, the research outcome is expected to provide critical contributions for the development of potential therapeutic intervention that can minimize tissue damage caused by viral hepatitis and immune disorders.
Professor Shin said, “This is a novel research case that discovered the clinical significance of bystander immune cell activation, which was previously unknown. We will continue to work on establishing treatments which could prevent tissue damage in viral and immune diseases in the future.”
This research was published in Immunity on January 2.
Figure 1. Graphical abstract
2018.03.06 View 6317 -
Cellular Mechanism for Severe Viral Hepatitis Identified
(Professor Shin(left) and Professor Jung)
KAIST medical scientists identified a cellular mechanism causing inflammatory changes in regulatory T cells that can lead to severe viral hepatitis. Research on this mechanism will help further understand the nature of various inflammatory diseases and lead to the development of relevant clinical treatments.
It is known that activated immune cells of patients with viral hepatitis destroy hepatocyte, but its regulatory mechanism has not yet been described.
Regulatory T cells inhibit activation of other immune cells and thus are important for homeostasis of the immune system. However, recent studies contradictorily show that immune inhibitory functions of regulatory T cells weaken in inflammatory conditions and the cells secrete inflammatory cytokines in response. Meanwhile, such a phenomenon was not observed in viral hepatitis including types A, B and C.
The team focused on changes in regulatory T cells in patients with viral hepatitis and discovered that regulatory T cells undergo inflammatory changes to secrete inflammatory cytokines (protein secreted by immune cells) called TNF. They also proved regulatory T cells that secrete TNF contribute to the progression of viral hepatitis.
The team confirmed that regulatory T cells of acute hepatitis A patients have reduced immune-inhibitory functions. Instead, their regulatory T cells secrete TNF. Through this research, the team identified a molecular mechanism for changes in regulatory T cells and identified the transcription factor regulating the process. Furthermore, the team found similar changes to be also present in hepatitis B and C patients.
A KAIST immunology research team led by Professors Eui-Cheol Shin and Min Kyung Jung at the Graduate School of Medical Science & Engineering conducted this translational research with teams from Chungnam National University and Yonsei University to identify the mechanism in humans, instead of using animal models. The research was described in Gastroenterology last December.
Professor Shin said, “This is the first research on regulatory T cells that contributes to hepatocyte damage in viral hepatitis.” He continued, “It is significant for identifying the cells and the molecules that can be used as effective treatment targets for viral hepatitis in the future. This research was funded by the Samsung Science and Technology Foundation.
(Figure1: Treg cells from acute hepatitis A (AHA) patients produce tumor necrosis factor (TNF) andhave reduced suppressive activity. These changes are due to a decrease in FoxP3 transcription factor and an increase in RORγt transcription factor. TNF-producing Treg cells are associated with severe liver injury in AHA patients.)
(Figure 2: A higher proportion of Treg cells from patients with acute hepatitis A, compared with healthy controls, produced TNF upon stimulation with anti-CD3 and anti-CD2. This study reports the presence and the significance of TNF-producing Treg cells for the first time in human patients.)
2018.01.18 View 7715 -
President Shin Reaffirms Innovation Initiatives in New Year Speech
(President Shin and representatives of faculty, students, staff celebrate the New Year in a reception held on January 2 at the auditorium.)
The KAIST community gathered to celebrate a fresh start for the year 2018. At the ceremony, held in the auditorium on January 2, members of KAIST community reaffirmed their commitment to be the trailblazers of Korea and beyond through unwavering innovations.
President Sung-Chul Shin presented his new vision and plan in his New Year speech, which focused on innovation for enhancing institutional competitiveness and global visibility. He said that as you are the future of KAIST, KAIST is the future of Korea. KAIST’s vision for a better future will have a significant impact on national progress and beyond. He stressed that innovation in the five pillars of education, research, technology commercialization, globalization, and future strategy will further advance the excellence of KAIST.
At the ceremony, President Shin also presented the award for ‘the KAISTian of the Year’ to Professor YongKeun Park of the Department of Physics. The annual award recognizes a distinguished professor whose academic accomplishments made the most significant impact.
In his New Year speech, President Shin said that the year 2018 will provide an opportunity to take a leap forward for becoming a ‘Global Value Creative, World-Leading University. The Vision 2031 Committee endorsed the five innovation initiatives to fulfill KAIST’s long-term vision and will open its recommendations to the public on March 20.
Educational innovation tops the initiatives. President Shin explained that the future of Korea is in the hands of talented individuals in science and technology, emphasizing the need to nurture creative, transdisciplinary talents with the capacity to enhance the social value of science and technology.
To this end, KAIST will establish a new undergraduate non-departmental program for transdisciplinary education. This plan will eventually provide students with more options in choosing their major, as well as help students build a strong foundation in basic science and engineering and encourage multidisciplinary approaches.
For creating an innovative institutional research infrastructure, KAIST plans to build a Network of Excellence for the Fourth Industrial Revolution (NExFire) for convergence research. The plan of ‘Cross-Generational Collaborative Labs,’ will bring out a new collaboration platform by pairing up senior and junior faculty. President Shin said it will be a stepping stone to extend the spectrum of knowledge without any cessation.
For technology commercialization, KAIST will maximize its intellectual property and economic value by stimulating technology-invested companies and startups. Close cooperation with venture capitalists at home and abroad will further accelerate the commercialization drive at KAIST.
Saying that the globalization is no long an option but a necessity, he stressed KAIST will strengthen its efforts to established a bilingual campus. “KAIST will make every effort to create a more welcoming and comfortable atmosphere for the international community and their families. We will expand benefits to our international community, such as access to the KAIST Child Care Center and collaboration with the Taejon Christian International School (TCIS),” he said. President Shin added he will further expand global networks and partnerships this year, participating in a diverse range of international events at home and abroad for increasing global visibility.
He also said that well-designed future strategies will complete innovation initiatives. The Future Strategy Research Center will serve as a think tank for identifying future agendas, establishing strategies and advocating for them.
In addition to the five innovation initiatives, President Shin emphasized a new organizational culture that embraces inclusiveness and mutual respect among all of the members of KAIST.
“So far, the ideal qualifications expected of KAISTians have included creativity and a challenging spirit. From now on, we will nurture talents with a focus on the 3Cs: Creativity, Challenge, and Caring. I would like to make a campus in which all members care for each other to help attain mutual growth with warmth and respect," he said.
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2018.01.02 View 7728 -
Unlocking the Keys to Parkinson's Disease
A KAIST research team has identified a new mechanism that causes the hallmark symptoms of Parkinson’s disease, namely tremors, rigidity, and loss of voluntary movement.
The discovery, made in collaboration with Nanyang Technological University in Singapore, presents a new perspective to three decades of conventional wisdom in Parkinson’s disease research. It also opens up new avenues that can help alleviate the motor problems suffered by patients of the disease, which reportedly number more than 10 million worldwide. The research was published in Neuron on August 30.
The research team was led by Professor Daesoo Kim from the Department of Biological Sciences at KAIST and Professor George Augustine from the Lee Kong Chian School of Medicine at NTU. Dr. Jeongjin Kim, a former postdoctoral fellow at KAIST who now works at the Korea Institute of Science and Technology (KIST), is the lead author.
It is known that Parkinson’s disease is caused by a lack of dopamine, a chemical in the brain that transmits neural signals. However, it remains unknown how the disease causes the motor
Smooth, voluntary movements, such as reaching for a cup of coffee, are controlled by the basal ganglia, which issue instructions via neurons (nerve cells that process and transmit information in the brain) in the thalamus to the cortex. These instructions come in two types: one that triggers a response (excitatory signals) and the other that suppresses a response (inhibitory signals). Proper balance between the two controls movement.
A low level of dopamine causes the basal ganglia to severely inhibit target neurons in the thalamus, called an inhibition. Scientists have long assumed that this stronger inhibition causes the motor problems of Parkinson’s disease patients.
To test this assumption, the research team used optogenetic technology in an animal model to study the effects of this increased inhibition of the thalamus and ultimately movement. Optogenetics is the use of light to control the activity of specific types of neurons within the brain.
They found that when signals from the basal ganglia are more strongly activated by light, the target neurons in the thalamus paradoxically became hyperactive. Called rebound excitation, this hyperactivity produced abnormal muscular stiffness and tremor. Such motor problems are very similar to the symptoms of Parkinson’s disease patients. When this hyperactivity of thalamic neurons is suppressed by light, mice show normal movments without Parkinson’s disease symptoms. Reducing the levels of activity back to normal caused the motor symptoms to stop, proving that the hyperactivity caused the motor problems experienced by Parkinson’s disease patients.
Professor Kim at KAIST said, “This study overturns three decades of consensus on the provenance of Parkinsonian symptoms.” The lead author, Dr Jeongjin Kim said, “The therapeutic implications of this study for the treatment of Parkinsonian symptoms are profound. It may soon become possible to remedy movement disorders without using L-DOPA, a pre-cursor to dopamine.”
Professor Augustine at NTU added, “Our findings are a breakthrough, both for understanding how the brain normally controls the movement of our body and how this control goes awry during Parkinson’s disease and related dopamine-deficiency disorders.”
The study took five years to complete, and includes researchers from the Department of Bio & Brain Engineering at KAIST.
The research team will move forward by investigating how hyperactivity in neurons in the thalamus leads to abnormal movement, as well as developing therapeutic strategies for the disease by targeting this neural mechanism.
Figure abstract: Inhibitory inputs from the basal ganglia inhibit thalamic neurons (upper). In low-dopamine states, like PD, rebound firing follows inhibition and causes movement disorders (middle). The inhibition of rebound firing alleviates PD-like symptoms in a mouse model of PD.
2017.09.22 View 9468