Biology subjects

Oh, S.-J.

Publications and source records attributed to Oh, S.-J..

8 recordsLinked to original sources

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↗

bioRxiv2023

Discrete projections from MCH neurons mediate anti-parkinsonian effects of acupuncture

Parkinsons disease (PD) presents with typical motor dysfunction and non-motor symptoms, including memory loss. Although acupuncture is suggested as an alternative therapy for PD, its neuroanatomical mechanisms remain unclear. We demonstrate that acupuncture ameliorates both motor and memory deficits in PD mice through activation of melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus and zona incerta (LH/ZI)--MCHLH/ZI-- via nerve conduction. We identify two distinct subpopulations of MCHLH/ZI projecting to the substantia nigra and hippocampus, each of which is responsible for controlling motor and memory function. This effect can be attributed to MCH-mediated recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, MCHLH/ZI constitutes not only the neuroanatomical basis of acupuncture but also a potential cellular target for treating both motor and non-motor PD symptoms. One-Sentence SummaryAcupuncture alleviates both motor and non-motor symptoms in Parkinsons disease by activating two distinct MCH projections.

neuroscience↗

bioRxiv2021

Differential receptor crosstalk in DRD1-DRD2 heterodimer upon phasic and tonic dopamine signals

In response to phasic and tonic release, dopamine neurotransmission is regulated by its receptor subtypes, mainly dopamine receptor type 1 and 2 (DRD1 and DRD2). These dopamine receptors are known to form a heterodimer, however the receptor crosstalk between DRD1 and DRD2 was only suspected by measuring their downstream signaling products, due to the lack of methodology for selectively detecting individual activity of different dopamine receptors. Here, we develop red DRD1 sensor (R-DRD1) and green DRD2 sensor (G-DRD2) which can specifically monitor the real-time activity of DRD1 and DRD2, and apply these multicolor sensors to directly measure the receptor crosstalk in the DRD1-DRD2 heterodimer. Surprisingly, we discover that DRD1 activation in the heterodimer is inhibited only at micromolar phasic concentration of dopamine, while DRD2 activation is selectively inhibited at nanomolar tonic dopamine level. Differential receptor crosstalk in the DRD1-DRD2 heterodimer further modulates their downstream cAMP level. These data imply a novel function of the DRD1-DRD2 heterodimer at physiological dopamine levels of phasic and tonic release. Our approach utilizing multicolor receptor sensors will be useful to discover novel function of GPCR heterodimers.

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↗

bioRxiv2021

Astrocytes render memory flexible

Cognitive flexibility is an essential ability to adapt to changing environment and circumstances. NMDAR has long been implicated in cognitive flexibility, but the precise molecular and cellular mechanism is not well understood. Here, we report that astrocytes regulate NMDAR tone through Best1-mediated glutamate and D-serine release, which is critical for cognitive flexibility. Co-release of D-serine and glutamate is required for not only homosynaptic LTD but also heterosynaptic LTD, which is induced at unstimulated synapses upon release of norepinephrine and activation of astrocytic 1-AR during homosynaptic LTP. Remarkably, heterosynaptic LTD at unstimulated synapses during memory acquisition is required for later repotentiation LTP during reversal learning, laying a foundation for flexible memory and cognitive flexibility. Our study sheds light on the pivotal role of astrocytes in orchestrating multiple synapses during memory formation and determining the fate of consolidated memory to be retained as a flexible memory. HighlightsO_LIAstrocytes regulate NMDAR tone via Best1-mediated glutamate and D-serine release C_LIO_LIActivation of astrocytic 1-AR induces heterosynaptic LTD via NMDAR tone C_LIO_LIHeterosynaptic LTD is required for repotentiation LTP and spatial reversal learning C_LIO_LIAstrocytic regulation of NMDAR tone is critical for metaplasticity and flexible memory C_LI

neuroscience↗

bioRxiv2020

CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson's disease

To date, no publicly available disease-modifying therapy for Parkinsons disease has been developed. This can be partly attributed to the absence of techniques for in vivo deletion of the SNCA gene (encoding -synuclein), which is one of the key players in Parkinsons disease pathology. In particular, A53T-mutated SNCA (A53T-SNCA) is one of the most studied familial pathologic mutations in Parkinsons disease. Here we utilized a recently discovered genome editing technique, CRISPR/Cas9, to delete A53T-SNCA in vitro and in vivo. Among various CRISPR/Cas9 systems, SaCas9-KKH with a single guide RNA (sgRNA) targeting A53T-SNCA was packaged into adeno-associated virus. Adeno-associated virus carrying SaCas9-KKH significantly reduced A53T-SNCA levels in A53T-SNCA-overexpressed HEK293T cells, without off-target effects on wild-type SNCA. Furthermore, we tested the techniques in vivo therapeutic potential in a viral A53T-SNCA overexpression rat model of Parkinsons disease. Gene deletion of A53T-SNCA significantly prevented the overexpression of -synuclein, dopaminergic neurodegeneration, and parkinsonian motor symptoms, whereas a negative control without sgRNA did not. Our findings propose CRISPR/Cas9 system as a potential therapeutic tool for A53T-SNCA familial Parkinsons disease.

genetics↗

bioRxiv2020

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson's disease

Background and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinsons disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD. Experimental ApproachWe designed and synthesized -aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates. Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the -aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates. Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD. Representative Schematic O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY What is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor. MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis. What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD. KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates. What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinsons disease. Reversible MAO-B inhibitors could be more effective for treatment of Parkinsons disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

pharmacology and toxicology↗

bioRxiv2018

The effect of a free radical scavenger on oxidation stress in partial bladder outlet obstruction and its relief in a rat model

AIMSTo investigate the effect of a free radical scavenger (tempol) after relief of partial bladder outlet obstruction (pBOO) on bladder function in a rat model.\n\nMETHODSpBOO was induced in 50 eight-week-old female Sprague-Dawley rats and relieved 3 weeks later. The rats were divided randomly into 5 groups: sham-operated, tempol-treated for 1 week (Treat-1w) or 3 weeks (Treat-3w), and no treatment for 1 week (nonTreat-1w) or 3 weeks (nonTreat-3w). Awaken cystometrograms were obtained 1 or 3 weeks after relief according to the grouping. The bladders were isolated and weighed. H&E, Massons trichrome and TUNEL staining were used to analyze histological changes. The oxidative stress assessed using malondialdehyde. The expression of beta-3 adrenoreceptor was examined by Western blotting.\n\nRESULTSThe tempol-treated groups exhibited a significant decrease in the number of IDCs per voiding cycle (nonTreat-1w vs. Treat-1w, 1.18{+/-}0.82 vs. 0.36{+/-}0.40, P=0.010; nonTreat-3w vs. Treat-3w, 1.51{+/-}0.69 vs. 0.23{+/-}0.25, P=0.002). The thickness and collagen fiber deposition of the detrusor muscle layer was significantly decreased in the treated groups. Apoptosis detected was mainly observed in the urothelial cell layer, although the rate of apoptosis was significantly decreased in the treated groups (48.9{+/-}3.36% vs. 32.7{+/-}11.10%, P=0.024; 25.8{+/-}4.67% vs. 15.7{+/-}9.83%, P=0.314). The tempol-treated groups showed significant decreases in the MDA concentrations at both 1 and 3 weeks after relief. The expression of the beta-3 adrenoreceptor was increased in the tempol-treated rats.\n\nCONCLUSIONSIschemic reperfusion injury after relief of pBOO caused histological and functional changes in the bladder. Free radical scavenger treatment prevented this oxidative stress.

biochemistry↗