研究者詳細 - 三澤　日出巳

論文 - 三澤　日出巳

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X-ray fluoroscopy-based kinematic analysis of quadrupedal locomotion in slow and fast fatigue-resistant motor neuron-deleted mice.

Ono, A., Inomata, D., Ohgaki, L., Koyama, T., Maeno, A., Misawa, H. Ogihara, N.

Muscle & Nerve 71 257 - 264 2024年12月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り

NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.

Hoshino, T., Mukai, A., Yamashita, H., Misawa, H., Urushitani, M., Tashiro, Y., Matsuzawa, S. Takahashi, R.

Mol. Brain 17 77 2024年10月

研究論文（学術雑誌）, 共著, 査読有り

Type selective ablation of postnatal slow and fast fatigue-resistant motor neurons in mice induces late onset kinetic and postural tremor following fiber-type transition and myopathy.

Misawa, H., Kamishima, K., Koyama, T., Ohgaki, L., Morisaki, Y., Yamanaka, K., Itohara, S., Sawano, S., Mizunoya, W. Ogihara, N.

Exp. Neurol. 376 114772 2024年04月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り

Suppression of neuroinflammation by coffee component pyrocatechol via inhibition of NF-κB in microglia.

Murata, T., Tago, K., Miyata, K., Moriwaki, Y., Misawa, H., Kobata, K., Nakazawa, Y., Tamura, H. Funakoshi-Tago, M.

Int. J. Mol. Sci. 25 316 2023年12月

研究論文（学術雑誌）, 共著, 査読有り

Depletion of perivascular macrophages delays ALS disease progression by ameliorating blood-spinal cord barrier impairment in SOD1G93A mice

Adachi K, Miyata K, Chida Y, Hirose M, Morisaki Y, Yamanaka K, Misawa H

Front Cell Neurosci 17 1291673 2023年11月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

LAG-3 expression in microglia regulated by IFN-γ/STAT1 pathway and metalloproteases

Morisaki Y, Ohshima M, Suzuki H, Misawa H

Front Cell Neurosci 17 1308972 2023年11月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

GTS-21 enhances regulatory T cell development from T cell receptor-activated human CD4+ T cells exhibiting varied levels of CHRNA7 and CHRFAM7A expression

Mashimo M, Fujii T, Ono S, Moriwaki Y, Misawa H, Azami T, Kasahara T, Kawashima K

Int J Mol Sci 24 12257 2023年07月

研究論文（学術雑誌）, 共著, 査読有り

Lysophosphatidic acid stimulates pericyte migration via LPA receptor 1

Yonezu Y, Tanabe S, Misawa H, Muramatsu R

Biochem Biophys Res Commun 618 61 - 66 2022年08月

研究論文（学術雑誌）, 共著, 査読有り

Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases.

Yamamotoya T, Hasei S, Akasaka Y, Ohata Y, Nakatsu Y, Kanna M, Fujishiro M, Sakoda H, Ono H, Kushiyama A, Misawa H, Asano T

Scientific reports 12 （ 1 ） 1966 2022年02月

研究論文（学術雑誌）, 共著, 査読有り

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Regulation of immune functions by non-neuronal acetylcholine (Ach) via muscarinic and nicotinic ach receptors

Mashimo M., Moriwaki Y., Misawa H., Kawashima K., Fujii T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 22 （ 13 ） 2021年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 16616596

Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs.

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Competitive inhibition of the high-affinity choline transporter by tetrahydropyrimidine anthelmintics

Okuda T., Nomura Y., Konishi A., Misawa H.

European Journal of Pharmacology （European Journal of Pharmacology） 898 173986 2021年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00142999

The high-affinity choline transporter CHT1 mediates choline uptake, the rate-limiting and regulatory step in acetylcholine synthesis at cholinergic presynaptic terminals. CHT1-medated choline uptake is specifically inhibited by hemicholinium-3, which is a type of choline analog that acts as a competitive inhibitor. Although the substrate choline and the inhibitor hemicholinium-3 are well-established ligands of CHT1, few potent ligands other than choline analogs have been reported. Here we show that tetrahydropyrimidine anthelmintics, known as nicotinic acetylcholine receptor agonists, act as competitive inhibitors of CHT1. A ligand-dependent trafficking assay in cell lines expressing human CHT1 was designed to search for CHT1 ligands from a collection of biologically active compounds. We found that morantel as well as other tetrahydropyrimidines, pyrantel and oxantel, potently inhibits the high-affinity choline uptake activity of CHT1 in a competitive manner similar to the inhibitor hemicholinium-3. They also inhibit the high-affinity choline transporter from the nematode Caenorhabditis elegans. Finally, tetrahydropyrimidines potently inhibit the high-affinity choline uptake in rat brain synaptosomes at a low micromolar level, resulting in the inhibition of acetylcholine synthesis. The rank order of potency in synaptosomes is as follows: morantel > pyarantel > oxantel (Ki = 1.3, 5.7, and 8.3 μM, respectively). Our results reveal that tetrahydropyrimidine anthelmintics are novel CHT1 ligands that inhibit the high-affinity choline uptake for acetylcholine synthesis in cholinergic neurons.

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Stagnation of glymphatic interstitial fluid flow and delay in waste clearance in the SOD1-G93A mouse model of ALS

Hirose M., Asano M., Watanabe-Matsumoto S., Yamanaka K., Abe Y., Yasui M., Tokuda E., Furukawa Y., Misawa H.

Neuroscience Research （Neuroscience Research） 171 74 - 82 2021年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01680102

© 2020 The Author(s) Overexpression and mislocalization of aquaporin-4 (AQP4) in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) have previously been reported. However, how alterations of AQP4 affect interstitial bulk flow in the brain and spinal cord, the so-called glymphatic system, is unclear. Here, we report an enhanced accumulation of disease-associated SOD1 species including SOD1 oligomers in SOD1G93A;AQP4−/− mice compared with SOD1G93A mice during ALS disease progression, as analyzed by sandwich ELISA. By directly injecting SOD1 oligomers into the spinal cord parenchyma, we observed a significantly larger delay in clearance of biotinylated or fluorescent-labeled SOD1 oligomers in AQP4−/− mice than in wild-type mice. Furthermore, when we injected the fluorescent-labeled tracer protein ovalbumin into the cisterna magna and analyzed the tracer distribution in the cervical spinal cord, approximately 35 % processing ability was found to be reduced in SOD1G93A mice compared to wild-type mice. These results suggest that the glymphatic system is abnormal and that waste clearance is delayed in SOD1G93A mice.

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Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane

Moriwaki Y., Kubo N., Watanabe M., Asano S., Shinoda T., Sugino T., Ichikawa D., Tsuji S., Kato F., Misawa H.

Scientific Reports 10 （ 1 ） 11996 - 11996 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

© 2020, The Author(s). α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and regarded as potential therapeutic targets for neurodegenerative conditions, such as Alzheimer’s disease and schizophrenia. Yet, despite the assumed pathophysiological importance of the α7 nAChR, molecular physiological characterization remains poorly advanced because α7 nAChR cannot be properly folded and sorted to the plasma membranes in most mammalian cell lines, thus preventing the analyses in heterologous expression system. Recently, ER-resident membrane protein NACHO was discovered as a strong chaperone for the functional expression of α7 nAChR in non-permissive cells. Ly6H, a brain-enriched GPI-anchored neurotoxin-like protein, was reported as a novel modulator regulating intracellular trafficking of α7 nAChR. In this study, we established cell lines that stably and robustly express surface α7 nAChR by introducing α7 nAChR, Ric-3, and NACHO cDNA into HEK293 cells (Triple α7 nAChR/RIC-3/NACHO cells; TARO cells), and re-evaluated the function of Ly6H. We report here that Ly6H binds with α7 nAChRs on the cell membrane and modulates the channel activity without affecting intracellular trafficking of α7 nAChR.

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Lysophosphatidic acid stimulates pericyte migration via LPA receptor 1.

Yonezu, Y., Tanabe, S., Misawa, H., Muramatsu, R.

Biochem. Biophys. Res. Commun. 618 61 - 66 2020年08月

研究論文（学術雑誌）, 共著, 査読有り

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Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model

Abe Y., Ikegawa N., Yoshida K., Muramatsu K., Hattori S., Kawai K., Murakami M., Tanaka T., Goda W., Goto M., Yamamoto T., Hashimoto T., Yamada K., Shibata T., Misawa H., Mimura M., Tanaka K.F., Miyakawa T., Iwatsubo T., Hata J.I., Niikura T., Yasui M.

Acta Neuropathologica Communications 8 （ 1 ） 67 - 67 2020年05月

研究論文（学術雑誌）, 共著, 査読有り

© 2020 The Author(s). Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

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Minireview: Divergent roles of α7 nicotinic acetylcholine receptors expressed on antigen-presenting cells and CD4+ T cells in the regulation of T cell differentiation

Mashimo M., Fujii T., Ono S., Moriwaki Y., Misawa H., Kawashima K.

International Immunopharmacology 82 106306 - 106306 2020年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15675769

© 2020 Elsevier B.V. α7 nAChRs expressed on immune cells regulate antigen-specific antibody and proinflammatory cytokine production. Using spleen cells from ovalbumin (OVA)-specific T cell receptor transgenic DO11.10 mice and the α7 nAChR agonist GTS-21, investigation of (1) antigen processing-dependent and (2) -independent, antigen presenting cell (APC)-dependent, naïve CD4+ T cell differentiation, as well as (3) non-specific APC-independent, anti-CD3/CD28 mAbs-induced CD4+ T cell differentiation, revealed the differential roles of α7 nAChRs expressed on T cells and APCs in the regulation of CD4+ T cell differentiation. GTS-21 suppressed OVA-induced antigen processing- and APC-dependent differentiation into regulatory T cells (Tregs) and effector T cells (Th1, Th2 and Th17) without affecting OVA uptake or cell viability. By contrast, GTS-21 upregulated OVA peptide-induced antigen processing-independent T cell differentiation into all lineages. During anti-CD3/CD28 mAbs-induced T cell differentiation in the presence of polarizing cytokines, GTS-21 promoted wild-type T cell differentiation into all lineages, but did not affect α7 nAChR-deficient T cell differentiation. These results demonstrate (1) that α7 nAChRs on APCs downregulate T cell differentiation by inhibiting antigen processing and thereby interfering with antigen presentation; and (2) that α7 nAChRs on T cells upregulate differentiation into Tregs and effector T cells. Thus, the divergent roles of α7 nAChRs on APCs and T cells likely regulate the intensity of immune responses. These findings suggest the possibility of using α7 nAChR agonists to harvest greater numbers of Tregs and Th1 and Th2 cells for adoptive immune therapies for treatment of autoimmune diseases and cancers.

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Oxidative misfolding of Cu/Zn-superoxide dismutase triggered by non-canonical intramolecular disulfide formation

Anzai I., Tokuda E., Handa S., Misawa H., Akiyama S., Furukawa Y.

Free Radical Biology and Medicine （Free Radical Biology and Medicine） 147 187 - 199 2020年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 08915849

© 2019 Elsevier Inc. Misfolded Cu/Zn-superoxide dismutase (SOD1) is a pathological species in a subset of amyotrophic lateral sclerosis (ALS). Oxidative stress is known to increase in affected spinal cords of ALS and is thus considered to cause damages on SOD1 leading to the misfolding and aggregation. Despite this, it still remains elusive what triggers misfolding of SOD1 under oxidizing environment. Here, we show that a thiol group of Cys111 in SOD1 is oxidized to a sulfenic acid with hydrogen peroxide and reveal that further dissociation of the bound metal ions from the oxidized SOD1 allows another free Cys residue (Cys6) to nucleophilically attack the sulfenylated Cys111. As a result, an intra-molecular disulfide bond forms between Cys6 and Cys111. Such an abnormal SOD1 with the non-canonical disulfide bond was conformationally extended with significant cytotoxicity as well as high propensity to aggregate. Taken together, we propose a new model of SOD1 misfolding under oxidizing environment, in which formation of the non-canonical intramolecular disulfide bond plays a pivotal role.

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Distinct roles of α7 nAChRs in antigen-presenting cells and CD4+ T cells in the regulation of T cell differentiation

Mashimo M., Komori M., Matsui Y., Murase M., Fujii T., Takeshima S., Okuyama H., Ono S., Moriwaki Y., Misawa H., Kawashima K.

Frontiers in Immunology （Frontiers in Immunology） 10 （ MAY ） 1102 - 1102 2019年

研究論文（学術雑誌）, 共著, 査読有り

Copyright © 2019 Mashimo, Komori, Matsui, Murase, Fujii, Takeshima, Okuyama, Ono, Moriwaki, Misawa and Kawashima. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. It is now apparent that immune cells express a functional cholinergic system and that α7 nicotinic acetylcholine receptors (α7 nAChRs) are involved in regulating T cell differentiation and the synthesis of antigen-specific antibodies and proinflammatory cytokines. Here, we investigated the specific function α7 nAChRs on T cells and antigen presenting cells (APCs) by testing the effect of GTS-21, a selective α7 nAChR agonist, on differentiation of CD4+ T cells from ovalbumin (OVA)-specific TCR transgenic DO11.10 mice activated with OVA or OVA peptide323−339 (OVAp). GTS-21 suppressed OVA-induced antigen processing-dependent development of CD4+ regulatory T cells (Tregs) and effector T cells (Th1, Th2, and Th17). By contrast, GTS-21 up-regulated OVAp-induced antigen processing-independent development of CD4+ Tregs and effector T cells. GTS-21 also suppressed production of IL-2, IFN-γ, IL-4, IL-17, and IL-6 during OVA-induced activation but, with the exception IL-2, enhanced their production during OVAp-induced activation. In addition, during antigen-nonspecific, APC-independent anti-CD3/CD28 antibody-induced CD4+ polyclonal T cell activation in the presence of respective polarizing cytokines, GTS-21 promoted development of all lineages, which indicates that GTS-21 also acts via α7 nAChRs on T cells. These results suggest 1) that α7 nAChRs on APCs suppress CD4+ T cell activation by interfering with antigen presentation through inhibition of antigen processing; 2) that α7 nAChRs on CD4+ T cells up-regulate development of Tregs and effector T cells; and that α7 nAChR agonists and antagonists could be potentially useful agents for immune response modulation and enhancement.

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Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1.

Reiko Matsuura, Hiroyuki Kaji, Azusa Tomioka, Takashi Sato, Hisashi Narimatsu, Yasuhiro Moriwaki, Hidemi Misawa, Kohzoh Ima, Shoutaro Tsuji.

Scientific Reports 8 14251 2018年09月

研究論文（学術雑誌）, 共著, 査読有り

The anti-mesothelioma mAb SKM9-2 recognizes the sialylated protein HEG homolog 1 (HEG1). HEG1 is a 400 kDa mucin-like membrane protein found on mesothelioma. SKM9-2 can detect mesothelioma more specifically and sensitively than other antibodies against current mesothelioma markers; therefore, SKM9-2 would be likely useful for the precise detection and diagnosis of malignant mesothelioma. In the present study, we investigated the epitope of SKM9-2. We analyzed the binding of SKM9-2 to truncated HEG1 and candidate epitope-fused glycosylphosphatidylinositol-anchor proteins. The epitope of SKM9-2 was identified as an O-glycosylated region, 893-SKSPSLVSLPT-903, in HEG1. An alanine scanning assay of the epitope showed that SKM9-2 bound to a simple epitope in HEG1, and the SKxPSxVS sequence within the epitope was essential for SKM9-2 recognition. Mass spectrometry analysis and lectin binding analysis of soluble epitope peptides indicated that the SKM9-2 epitope, in which Ser897 was not glycosylated, contained two disialylated core 1 O-linked glycan-modified serine residues, Ser893 and Ser900. Neuraminidase treatment analysis also confirmed that the epitope in mesothelioma cells contained a similar glycan modification. The specific detection of mesothelioma with SKM9-2 can thus be performed by the recognition of sialylated glycan modification in the specific region of HEG1.

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Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis

Watanabe-Matsumoto Saori, Moriwaki Yasuhiro, Okuda Takashi, Ohara Shinji, Yamanaka Koji, Abe Yoichiro, Yasui Masato, Misawa Hidemi

Neuroscience Research 133 48 - 57 2018年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0168-0102

Aquaporin-4 (AQP4) is abundantly expressed in the central nervous system and is involved in the water balance in the cellular environment. Previous studies have reported that AQP4 expression is upregulated in rat models of amyotrophic lateral sclerosis (ALS), a fatal disease that affects motor neurons in the brain and spinal cord. In this study, we report that astrocytic AQP4 overexpression is evident during the course of disease in the spinal cord of an ALS mouse model, as well as in tissue from patients with ALS. AQP4 overexpression appears to be specifically associated with ALS because it was not induced by other experimental manipulations that produced acute or chronic gliosis. In order to examine the contribution of AQP4 to ALS disease development, we crossed AQP4 knockout mice with a mouse model of ALS. Significant improvement in blood-brain barrier (BBB) permeability was observed in the AQP4-deficient ALS mouse model. However, the time to disease onset and total lifespan were reduced in the AQP4-deficient ALS mouse model. The contradictory results suggest that changes in AQP4 may be context-dependent and further studies are required to understand the precise contribution of brain water balance in ALS.

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