Biology subjects

Won, W.

Publications and source records attributed to Won, W..

6 recordsLinked to original sources

bioRxiv2025

H2O2-induced astrocytic collagen triggers neuronal death via fucosylation-dependent glial barrier formation upon ischemic stroke

The cascade of molecular and cellular events leading to neuronal death after a focal ischemic stroke remains enigmatic. Although astrocytes form glial barriers that may protect surrounding tissue, how barriers develop and contribute to neuronal death is unclear. Here, we show that H2O2 induces astrocytic type I collagen (COL1)-production via miR-29-mediated post-transcriptional and fucosylation-dependent post-translational regulations, leading to integrin activation and neuronal death. In photothrombosis (PT)-induced cortical stroke model, PT triggered H2O2-surge, astrogliosis, glial barrier formation, COL1 expression, fibrotic scarring, altered N-glycosylation, neuronal loss, and neurological deficits. Remarkably, these effects were reversed by astrocyte-specific COL1 or FUT8 gene-silencing or treatment with KDS12025, an H2O2-decomposing peroxidase enhancer. KDS12025s neuroprotective effects were also recapitulated in non-human primate stroke model. These findings delineate a previously unrecognized astrocyte-driven mechanism in which oxidative stress induces COL1 production, promoting neuronal death, and position H2O2 and astrocytic COL1 and FUT8 as promising therapeutic targets for ischemic stroke.

neuroscience↗

bioRxiv2024

Astrocytic hemoglobin is an H2O2-decomposing peroxidase and therapeutic target for Alzheimer's disease

Summary paragraphHemoglobin (Hb) is well-known for transporting oxygen in red blood cells within blood vessels1. Although Hb is also present in the brain2, its role remains poorly understood. Here, we show that Hb, found in astrocytes of neurodegenerative animal models and patients, displays significant antioxidant effects through its H2O2-decomposing peroxidase activity, and a small molecule enhancer boosts this activity, reducing aberrant H2O2 and mitigating H2O2-induced neurodegeneration. To counteract the harmful effects of aberrant H2O2-production in Alzheimers disease (AD), we developed KDS12025, a blood-brain barrier (BBB)-permeable small molecule that effectively enhances the peroxidase activity of Hb by a hundredfold, especially at a low level of Hb. KDS12025 and its analogs achieve this enhancement through its electron-donating amine group. KDS12025 reduces H2O2 levels in astrocytes, exhibits neuroprotective effects, and reverses memory impairment in AD models. Gene-silencing of Hb{beta} abrogates KDS12025s impact in both culture and animal models of AD. Moreover, KDS12025 prevented the death of dopaminergic neurons in a Parkinsons disease (PD) model without altering the oxygen-transporting function of Hb. KDS12025 extended survival and improved motor function even in the severe amyotrophic lateral sclerosis (ALS) mouse model. Our findings propose Hb as a new therapeutic target for neurodegenerative diseases, with KDS12025 emerging as a first-in-class drug candidate that enhances Hbs peroxidase activity to reduce H2O2. Boosting Hbs peroxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD, PD, and ALS with broad applicability for numerous oxidative-stress-driven diseases.

neuroscience↗

bioRxiv2024

Structure-guided engineering of a fast genetically encoded sensor for real-time H2O2 monitoring.

Hydrogen Peroxide (H2O2) is a central oxidant in redox biology due to its pleiotropic role in physiology and pathology. However, real-time monitoring of H2O2 in living cells and tissues remains a challenge. We address this gap with the development of an optogenetic hydRogen perOxide Sensor (oROS), leveraging the bacterial peroxide binding domain OxyR. Previously engineered OxyR-based fluorescent peroxide sensors lack the necessary sensitivity or response speed for effective real-time monitoring. By structurally redesigning the fusion of Escherichia coli (E. coli) ecOxyR with a circularly permutated green fluorescent protein (cpGFP), we created a novel, green-fluorescent peroxide sensor oROS-G. oROS-G exhibits high sensitivity and fast on-and-off kinetics, ideal for monitoring intracellular H2O2 dynamics. We successfully tracked real-time transient and steady-state H2O2 levels in diverse biological systems, including human stem cell-derived neurons and cardiomyocytes, primary neurons and astrocytes, and mouse neurons and astrocytes in ex vivo brain slices. These applications demonstrate oROSs capabilities to monitor H2O2 as a secondary response to pharmacologically induced oxidative stress, G-protein coupled receptor (GPCR)-induced cell signaling, and when adapting to varying metabolic stress. We showcased the increased oxidative stress in astrocytes via A{beta}-putriscine-MAOB axis, highlighting the sensors relevance in validating neurodegenerative disease models. oROS is a versatile tool, offering a window into the dynamic landscape of H2O2 signaling. This advancement paves the way for a deeper understanding of redox physiology, with significant implications for diseases associated with oxidative stress, such as cancer, neurodegenerative disorders, and cardiovascular diseases.

bioengineering↗

bioRxiv2021

Gabra5LHA Mediate Astrocytic GABA-induced Obesity via Decreasing Energy Expenditure

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

neuroscience↗

bioRxiv2021

Visualization of reactive astrocytes in living brain of Alzheimer's disease patient

An early appearance of reactive astrocytes is a hallmark of Alzheimers disease (AD)1,2, providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

neuroscience↗

bioRxiv2020

Platycodin D prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection in vitro by hindering membrane fusion

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to the global public health. Herbal medicines and their derived natural products have drawn much attention to treat COVID-19, but there has been no natural product showing inhibitory activity against SARS-CoV-2 infection with detailed mechanism. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection-routes via lysosome- and transmembrane protease, serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host-entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by a pharmacological inhibition or gene-silencing of NPC1, which is mutated in Niemann-Pick type C (NPC) patients displaying disrupted membrane cholesterol. Finally, readily available local foods or herbal medicines containing PG root show the similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that a brief disruption of membrane cholesterol can be a novel therapeutic approach against SARS-CoV-2 infection.

pharmacology and toxicology↗