Inflammation
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Editing Parkinson's Disease – KAIST Makes World's First Discovery of an Inflammatory RNA Editing Enzyme
< Professor Minee Choi of the Department of Brain and Cognitive Sciences (top left). Professor Sonia Gandhi (top right) and Professor Klenerman of the University College London (bottom right) >
Parkinson's disease (PD) is a neurodegenerative disorder in which the α-synuclein protein abnormally aggregates within brain cells, causing neuronal damage. Through international collaboration, researchers at KAIST have revealed that RNA editing plays a crucial role in regulating neuroinflammation, a key pathology of Parkinson's disease.
KAIST (represented by President Kwang-Hyung Lee) announced on the 27th of April that a research team led by Professor Minee L. Choi from the Department of Brain and Cognitive Sciences, in collaboration with University College London (UCL) and the Francis Crick Institute, discovered that the RNA editing enzyme ADAR1 plays an important role in controlling immune responses in astrocytes, glial cells that trigger protective reactions in the brain, and demonstrated that this mechanism is critically involved in the progression of Parkinson’s disease.
Professor Choi's research team created a co-culture model composed of astrocytes and neurons derived from stem cells originating from Parkinson's disease patients, in order to study the inflammatory responses of brain immune cells. They then treated the model with α-synuclein aggregates, which are known to cause Parkinson’s disease, and analyzed how the immune cells' inflammatory responses changed.
< Figure 1. Schematic diagram of the inflammatory RNA editing model in Parkinson's disease >
As a result, it was found that early pathological forms of α-synuclein, known as oligomers, activated the Toll-like receptor pathway, which acts as a danger sensor in astrocytes, as well as the interferon response pathway, an immune signaling network that combats viruses and pathogens. During this process, the RNA editing enzyme ADAR1 was expressed and transformed into an isoform with an altered protein structure and function.
Notably, the RNA editing activity of ADAR1, which normally functions to regulate immune responses during viral infections by converting adenosine (A) to inosine (I) through a process known as A-to-I RNA editing, was found to be abnormally focused on genes that cause inflammation rather than operating under normal conditions. This phenomenon was observed not only in the patient-derived neuron models but also in postmortem brain tissues from actual Parkinson’s disease patients.
< Figure 2. Experimental design and inflammatory response induction in astrocytes following treatment with α-synuclein oligomers (abnormally folded protein fragments) >
This directly proves that the dysregulation of RNA editing induces chronic inflammatory responses in astrocytes, ultimately leading to neuronal toxicity and pathological progression.
This study is significant in that it newly identified the regulation of RNA editing within astrocytes as a key mechanism behind neuroinflammatory responses. In particular, it suggests that ADAR1 could serve as a novel genetic target for the treatment of Parkinson’s disease.
It is also noteworthy that the study reflected actual pathological characteristics of patients by utilizing patient-specific induced pluripotent stem cell-based precision models for brain diseases.
Professor Minee L. Choi stated, “This study demonstrates that the regulator of inflammation caused by protein aggregation operates at the new layer of RNA editing, offering a completely different therapeutic strategy from existing approaches to Parkinson's disease treatment." She further emphasized, “RNA editing technology could become an important turning point in the development of therapeutics for neuroinflammation.”
< Figure 3. When treated with α-synuclein oligomers, the causative agent of Parkinson's disease, A-to-I RNA editing is induced to change genetic information by ADAR in patient-derived stem cell-differentiated glial cells, confirming that α-synuclein is likely to be associated with the progression of Parkinson's disease through RNA editing >
This study was published in Science Advances on April 11, with Professor Choi listed as a co-first author.
Paper Title: Astrocytic RNA editing regulates the host immune response to alpha-synuclein, Science Advances Vol.11, Issue 15. (DOI:10.1126/sciadv.adp8504)
Lead Authors: Karishma D’Sa (UCL, Co-First Author), Minee L. Choi (KAIST, Co-First Author), Mina Ryten (UCL, Corresponding Author), Sonia Gandhi (Francis Crick Institute, University of Cambridge, Corresponding Author)
This research was supported by the Brain Research Program and the Excellent Young Researcher Program of the National Research Foundation of Korea, as well as KAIST’s Daekyo Cognitive Enhancement Program.
2025.05.02 View 349 -
KAIST Develops Healthcare Device Tracking Chronic Diabetic Wounds
A KAIST research team has developed an effective wireless system that monitors the wound healing process by tracking the spatiotemporal temperature changes and heat transfer characteristics of damaged areas such as diabetic wounds.
On the 5th of March, KAIST (represented by President Kwang Hyung Lee) announced that the research team led by Professor Kyeongha Kwon from KAIST’s School of Electrical Engineering, in association with Chung-Ang University professor Hanjun Ryu, developed digital healthcare technology that tracks the wound healing process in real time, which allows appropriate treatments to be administered.
< Figure 1. Schematic illustrations and diagrams of real-time wound monitoring systems. >
The skin serves as a barrier protecting the body from harmful substances, therefore damage to the skin may cause severe health risks to patients in need of intensive care. Especially in the case of diabetic patients, chronic wounds are easily formed due to complications in normal blood circulation and the wound healing process. In the United States alone, hundreds of billions of dollars of medical costs stem from regenerating the skin from such wounds. While various methods exist to promote wound healing, personalized management is essential depending on the condition of each patient's wounds.
Accordingly, the research team tracked the heating response within the wound by utilizing the differences in temperature between the damaged area and the surrounding healthy skin. They then measured heat transfer characteristics to observe moisture changes near the skin surface, ultimately establishing a basis for understanding the formation process of scar tissue. The team conducted experiments using diabetic mice models regarding the delay in wound healing under pathological conditions, and it was demonstrated that the collected data accurately tracks the wound healing process and the formation of scar tissue.
To minimize the tissue damage that may occur in the process of removing the tracking device after healing, the system integrates biodegradable sensor modules capable of natural decomposition within the body. These biodegradable modules disintegrate within the body after use, thus reducing the risk of additional discomfort or tissue damage upon device removal. Furthermore, the device could one day be used for monitoring inside the wound area as there is no need for removal.
Professor Kyeongha Kwon, who led the research, anticipates that continuous monitoring of wound temperature and heat transfer characteristics will enable medical professionals to more accurately assess the status of diabetic patients' wounds and provide appropriate treatment. He further predicted that the implementation of biodegradable sensors allows for the safe decomposition of the device after wound healing without the need for removal, making live monitoring possible not only in hospitals but also at home.
The research team plans to integrate antimicrobial materials into this device, aiming to expand its technological capabilities to enable the observation and prevention of inflammatory responses, bacterial infections, and other complications. The goal is to provide a multi-purpose wound monitoring platform capable of real-time antimicrobial monitoring in hospitals or homes by detecting changes in temperature and heat transfer characteristics indicative of infection levels.
< Image 1. Image of the bioresorbable temperature sensor >
The results of this study were published on February 19th in the international journal Advanced Healthcare Materials and selected as the inside back cover article, titled "Materials and Device Designs for Wireless Monitoring of Temperature and Thermal Transport Properties of Wound Beds during Healing."
This research was conducted with support from the Basic Research Program, the Regional Innovation Center Program, and the BK21 Program.
2024.03.11 View 5708 -
A New Therapeutic Drug for Alzheimer’s Disease without Inflammatory Side Effects
Although Aduhelm, a monoclonal antibody targeting amyloid beta (Aβ), recently became the first US FDA approved drug for Alzheimer’s disease (AD) based on its ability to decrease Aβ plaque burden in AD patients, its effect on cognitive improvement is still controversial. Moreover, about 40% of the patients treated with this antibody experienced serious side effects including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H) that are likely related to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages.
These inflammatory side effects can cause neuronal cell death and synapse elimination by activated microglia, and even have the potential to exacerbate cognitive impairment in AD patients. Thus, current Aβ antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects.
To overcome these problems, a team of researchers at KAIST in South Korea has developed a novel fusion protein drug, αAβ-Gas6, which efficiently eliminates Aβ via an entirely different mechanism than Aβ antibody-based immunotherapy. In a mouse model of AD, αAβ-Gas6 not only removed Aβ with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments.
Their findings were published on August 4 in Nature Medicine.
Schematic of a chimeric Gas6 fusion protein. A single chain variable fragment (scFv) of
an Amyloid β (Aβ)-targeting monoclonal antibody is fused with a truncated receptor binding
domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL,
and MERTK) receptors, which are expressed by microglia and astrocytes.
“FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST.
“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” Prof. Kim and Chung said. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques.”
The professors and their team demonstrated that the resulting αAβ-Gas6 induced Aβ engulfment by activating not only microglial but also astrocytic phagocytosis since TAM phagocytic receptors are highly expressed by these two major phagocytes in the brain. Importantly, αAβ-Gas6 promoted the robust uptake of Aβ without showing any signs of inflammation and neurotoxicity, which contrasts sharply with the treatment using an Aβ monoclonal antibody. Moreover, they showed that αAβ-Gas6 substantially reduced excessive synapse elimination by microglia, consequently leading to better behavioral rescues in AD model mice.
“By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Aβ within the walls of the brain’s blood vessels, we also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Aβ without exacerbating CAA-related microhemorrhages.”
The resulting αAβ-Gas6 clears Aβ oligomers and fibrils without causing neurotoxicity (a-b, neurons: red, and fragmented axons: yellow) and proinflammatory responses (c, TNF release), which are conversely exacerbated by the treatment of an Aβ-targeting monoclonal antibody (Aducanumab).
Professors Kim and Chung noted, “We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.”
The number and total area of Aβ plaques (Thioflavin-T, green) were significantly reduced in αAβ-Gas6-treated AD mouse brains compared to Aducanumab-treated ones (a, b). The cognitive functions of AD model mice were significantly rescued by αAβ-Gas6 treatment, whereas Aducanumab-treated AD mice showed partial rescue in these cognitive tests (c-e).
Professors Kim and Chung founded “Illimis Therapeutics” based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Ab but also for Tau to treat AD symptoms.
This work was supported by KAIST and the Korea Health Technology R&D Project that was administered by the Korea Health Industry Development Institute (KHIDI) and the Korea Dementia Research Center (KDRC) funded by the Ministry of Health & Welfare (MOHW) and the Ministry of Science and ICT (MSIT), and KAIST.
Other contributors include Hyuncheol Jung and Se Young Lee, Sungjoon Lim, Hyeong Ryeol Choi, Yeseong Choi, Minjin Kim, Segi Kim, the Department of Biological Sciences, and the Korea Advanced Institute of Science and Technology (KAIST).
To receive more up-to-date information on this new development, follow “Illimis Therapeutics” on twitter @Illimistx.
2022.08.05 View 11712