Updated on 2024/03/28

写真a

 
IIDA Madoka
 
Organization
Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division for Advanced Medical Research Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor

Degree 1

  1. 博士(医学) ( 2014.11   名古屋大学 ) 

Research Areas 1

  1. Life Science / Neuroscience-general

Awards 1

  1. 第6回山本纊子賞

    2024.3   公益社団法人 日本女医会  

 

Papers 22

  1. Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies. International journal

    Yuki Fukami, Masahiro Iijima, Haruki H Koike, Satoru Yagi, Soma Furukawa, Naohiro Mouri, Jun Ouchida, Ayuka Murakami, Madoka Iida, Satoshi Yokoi, Atsushi Hashizume, Yohei Iguchi, Shiro Imagama, Masahisa Katsuno

    Neurology(R) neuroimmunology & neuroinflammation   Vol. 11 ( 2 ) page: e200199   2024.3

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    BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

    DOI: 10.1212/NXI.0000000000200199

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  2. Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy. International journal

    Tomoki Hirunagi, Hideaki Nakatsuji, Kentaro Sahashi, Mikiyasu Yamamoto, Madoka Iida, Genki Tohnai, Naohide Kondo, Shinichiro Yamada, Ayuka Murakami, Seiya Noda, Hiroaki Adachi, Gen Sobue, Masahisa Katsuno

    Journal of cachexia, sarcopenia and muscle   Vol. 15 ( 1 ) page: 159 - 172   2024.2

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    BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine-adenine-guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive. METHODS: We investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5 m/min) 5 days a week for 4 weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated. RESULTS: AR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P < 0.05) and survival (median survival 23.6 vs. 16.7 weeks, P < 0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P < 0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P < 0.05). We found that the exercise activated 5'-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells. CONCLUSIONS: Our findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.

    DOI: 10.1002/jcsm.13344

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  3. Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy. International journal

    Mayumi Kataoka, Kentaro Sahashi, Koyo Tsujikawa, Jun-Ichi Takeda, Tomoki Hirunagi, Madoka Iida, Masahisa Katsuno

    Neuroscience research   Vol. 194   page: 58 - 65   2023.9

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    Lower motor neuron degeneration is the pathological hallmark of spinal muscular atrophy (SMA), a hereditary motor neuron disease caused by loss of the SMN1 gene and the resulting deficiency of ubiquitously expressed SMN protein. The molecular mechanisms underlying motor neuron degeneration, however, remain elusive. To clarify the cell-autonomous defect in developmental processes, we here performed transcriptome analyses of isolated embryonic motor neurons of SMA model mice to explore mechanisms of dysregulation of cell-type-specific gene expression. Of 12 identified genes that were differentially expressed between the SMA and control motor neurons, we focused on Aldh1a2, an essential gene for lower motor neuron development. In primary spinal motor neuron cultures, knockdown of Aldh1a2 led to the formation of axonal spheroids and neurodegeneration, reminiscent of the histopathological changes observed in human and animal cellular models. Conversely, Aldh1a2 rescued these pathological features in spinal motor neurons derived from SMA mouse embryos. Our findings suggest that developmental defects due to Aldh1a2 dysregulation enhances lower motor neuron vulnerability in SMA.

    DOI: 10.1016/j.neures.2023.04.007

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  4. Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis

    Murakami Ayuka, Noda Seiya, Kazuta Tomoyuki, Hirano Satoko, Kimura Seigo, Nakanishi Hirotaka, Matsuo Koji, Tsujikawa Koyo, Iida Madoka, Koike Haruki, Sakamoto Kazuma, Hara Yuichiro, Kuru Satoshi, Kadomatsu Kenji, Shimamura Teppei, Ogi Tomoo, Katsuno Masahisa

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY   Vol. 9 ( 10 ) page: 1602 - 1615   2022.10

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    Language:Japanese   Publisher:Annals of Clinical and Translational Neurology  

    Objective: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. Methods: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. Results: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. Interpretation: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.

    DOI: 10.1002/acn3.51657

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  5. 球脊髄性筋萎縮症におけるアンドロゲン依存的な軸索脆弱性へのMID1の関与

    小椋 陽介, 佐橋 健太郎, 蛭薙 智紀, 飯田 円, 宮田 卓樹, 勝野 雅央

    臨床神経学   Vol. 62 ( Suppl. ) page: S415 - S415   2022.10

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    Language:Japanese   Publisher:(一社)日本神経学会  

  6. Clinical implication of denervation in sporadic inclusion body myositis. International journal

    Seiya Noda, Ayuka Murakami, Tomoyuki Kazuta, Satoko Hirano, Seigo Kimura, Hirotaka Nakanishi, Koji Matsuo, Koyo Tsujikawa, Shinichiro Yamada, Madoka Iida, Haruki Koike, Satoshi Kuru, Masahisa Katsuno

    Journal of the neurological sciences   Vol. 439   page: 120317 - 120317   2022.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    INTRODUCTION: Sporadic inclusion body myositis (sIBM) is often accompanied by signs suggestive of denervation on electromyography (EMG), which mimics neurogenic disorders. Hence, the current study aimed to assess reinnervation after denervation in sIBM and its clinical impllcation. METHODS: We retrospectively examined consecutive muscle biopsy specimens collected from 109 sIBM patients who were referred to our institution for diagnostic muscle biopsy from 2001 to 2018. Reinnervation after denervation in sIBM patients was assessed via muscle biopsy and EMG. The levels of acetylcholine receptor subunit γ (Chrng) and muscle-specific kinase (MuSK) mRNA, which are markers of denervation, were examined using real-time polymerase chain reaction. Response to treatment was defined as an increase of grade 1 or higher in two or more muscle groups as assessed using the Medical Research Council scale. RESULTS: In total, 93 (85.3%) of 109 sIBM patients had reinnervation after denervation on histological examination and/or EMG. The mean disease duration before biopsy was significantly longer in patients with reinnervation after denervation than in those without (p < 0.00001). Patients with denervation had significantly higher levels of Chrng and MuSK mRNA than those without. The proportion of patients who responded to immunosuppressive therapies was smaller in the patients with denervation than those without (p < 0.05). However, there was no significant difference regarding time from onset to using a walking aid between the two groups. DISCUSSION: Reinnervation after denervation is associated with disease duration and short-term response to therapy in individuals with sIBM.

    DOI: 10.1016/j.jns.2022.120317

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  7. Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy. International journal

    Yosuke Ogura, Kentaro Sahashi, Tomoki Hirunagi, Madoka Iida, Takaki Miyata, Masahisa Katsuno

    Cell death & disease   Vol. 13 ( 7 ) page: 601 - 601   2022.7

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    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset hereditary neurodegenerative disease caused by the expansions of CAG repeats in the androgen receptor (AR) gene. Androgen-dependent nuclear accumulation of pathogenic AR protein causes degeneration of lower motor neurons, leading to progressive muscle weakness and atrophy. While the successful induction of SBMA-like pathology has been achieved in mouse models, mechanisms underlying motor neuron vulnerability remain unclear. In the present study, we performed a transcriptome-based screening for genes expressed exclusively in motor neurons and dysregulated in the spinal cord of SBMA mice. We found upregulation of Mid1 encoding a microtubule-associated RNA binding protein which facilitates the translation of CAG-expanded mRNAs. Based on the finding that lower motor neurons begin expressing Mid1 during embryonic stages, we developed an organotypic slice culture system of the spinal cord obtained from SBMA mouse fetuses to study the pathogenic role of Mid1 in SBMA motor neurons. Impairment of axonal regeneration arose in the spinal cord culture in SBMA mice in an androgen-dependent manner, but not in mice with non-CAG-expanded AR, and was either exacerbated or ameliorated by Mid1 overexpression or knockdown, respectively. Hence, an early Mid1 expression confers vulnerability to motor neurons, at least by inducing axonogenesis defects, in SBMA.

    DOI: 10.1038/s41419-022-05001-6

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  8. Label-free morphological sub-population cytometry for sensitive phenotypic screening of heterogenous neural disease model cells. International journal

    Yuta Imai, Madoka Iida, Kei Kanie, Masahisa Katsuno, Ryuji Kato

    Scientific reports   Vol. 12 ( 1 ) page: 9296 - 9296   2022.6

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    Label-free image analysis has several advantages with respect to the development of drug screening platforms. However, the evaluation of drug-responsive cells based exclusively on morphological information is challenging, especially in cases of morphologically heterogeneous cells or a small subset of drug-responsive cells. We developed a novel label-free cell sub-population analysis method called "in silico FOCUS (in silico analysis of featured-objects concentrated by anomaly discrimination from unit space)" to enable robust phenotypic screening of morphologically heterogeneous spinal and bulbar muscular atrophy (SBMA) model cells. This method with the anomaly discrimination concept can sensitively evaluate drug-responsive cells as morphologically anomalous cells through in silico cytometric analysis. As this algorithm requires only morphological information of control cells for training, no labeling or drug administration experiments are needed. The responses of SBMA model cells to dihydrotestosterone revealed that in silico FOCUS can identify the characteristics of a small sub-population with drug-responsive phenotypes to facilitate robust drug response profiling. The phenotype classification model confirmed with high accuracy the SBMA-rescuing effect of pioglitazone using morphological information alone. In silico FOCUS enables the evaluation of delicate quality transitions in cells that are difficult to profile experimentally, including primary cells or cells with no known markers.

    DOI: 10.1038/s41598-022-12250-0

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  9. MORPHOLOGY-BASED EVALUATION FOR DRUG RESPONSES IN HETEROGENEOUS NEURAL CELL POPULATION

    Imai Yuta, Kanie Kei, Iida Madoka, Katsuno Masahisa, Kato Ryuji

    TISSUE ENGINEERING PART A   Vol. 28   page: S305 - S305   2022.4

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  10. Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis Reviewed

    Yamada Shinichiro, Hashizume Atsushi, Hijikata Yasuhiro, Ito Daisuke, Kishimoto Yoshiyuki, Iida Madoka, Koike Haruki, Hirakawa Akihiro, Katsuno Masahisa

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   Vol. 92 ( 10 ) page: 1072 - 1079   2021.10

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    Language:Japanese   Publisher:Journal of Neurology, Neurosurgery and Psychiatry  

    © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. Objective: We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS). Methods: We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment. Results: Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (r=-0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis. Conclusions: Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.

    DOI: 10.1136/jnnp-2020-324615

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  11. Titinを標的とした筋萎縮性側索硬化症患者のバイオマーカー開発

    山田 晋一郎, 橋詰 淳, 伊藤 大輔, 岸本 祥之, 鳥居 良太, 飯田 円, 勝野 雅央

    神経治療学   Vol. 38 ( 6 ) page: S261 - S261   2021.10

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    Language:Japanese   Publisher:(一社)日本神経治療学会  

  12. A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue-induced cocaine craving following prolonged abstinence. Reviewed

    Mitra S, Gobira PH, Werner CT, Martin JA, Iida M, Thomas SA, Erias K, Miracle S, Lafargue C, An C, Dietz DM

    Addiction biology   Vol. 26 ( 5 ) page: e13007   2021.9

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    DOI: 10.1111/adb.13007

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  13. Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS Reviewed

    Hirunagi Tomoki, Sahashi Kentaro, Tachikawa Kiyoshi, Leu Angel I., Nguyen Michelle, Mukthavaram Rajesh, Karmali Priya P., Chivukula Padmanabh, Tohnai Genki, Iida Madoka, Onodera Kazunari, Ohyama Manabu, Okada Yohei, Okano Hideyuki, Katsuno Masahisa

    MOLECULAR THERAPY-NUCLEIC ACIDS   Vol. 24   page: 1 - 10   2021.6

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    Language:Japanese   Publisher:Molecular Therapy - Nucleic Acids  

    Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by expansion of cytosine-adenine-guanine (CAG)-trinucleotide repeats in causative genes. These diseases include spinal and bulbar muscular atrophy (SBMA), Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias. Targeting expanded CAG repeats is a common therapeutic approach to polyQ diseases, but concomitant silencing of genes with normal CAG repeats may lead to toxicity. Previous studies have shown that CAG repeat-targeting small interfering RNA duplexes (CAG-siRNAs) have the potential to selectively suppress mutant proteins in in vitro cell models of polyQ diseases. However, in vivo application of these siRNAs has not yet been investigated. In this study, we demonstrate that an unlocked nucleic acid (UNA)-modified CAG-siRNA shows high selectivity for polyQ-expanded androgen receptor (AR) inhibition in in vitro cell models and that lipid nanoparticle (LNP)-mediated delivery of the CAG-siRNA selectively suppresses mutant AR in the central nervous system of an SBMA mouse model. In addition, a subcutaneous injection of the LNP-delivered CAG-siRNA efficiently suppresses mutant AR in the skeletal muscle of the SBMA mouse model. These results support the therapeutic potential of LNP-delivered UNA-modified CAG-siRNAs for selective suppression of mutant proteins in SBMA and other polyQ diseases. Mutant-allele selective suppression by CAG repeat-targeting oligonucleotides is a promising therapeutic approach to polyglutamine diseases. Hirunagi et al. demonstrate selective suppression of polyglutamine-expanded androgen receptor by lipid nanoparticle-mediated delivery of siRNA targeting CAG expansions in the mouse CNS of an SBMA mouse model.

    DOI: 10.1016/j.omtn.2021.02.007

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  14. Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence. Reviewed

    Werner CT, Mitra S, Auerbach BD, Wang ZJ, Martin JA, Stewart AF, Gobira PH, Iida M, An C, Cobb MM, Caccamise A, Salvi RJ, Neve RL, Gancarz AM, Dietz DM

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 117 ( 42 ) page: 26460 - 26469   2020.10

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    DOI: 10.1073/pnas.2006133117

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  15. Src Inhibition Attenuates Polyglutamine-mediated Neuromuscular Degeneration in Spinal and Bulbar Muscular Atrophy

    Iida Madoka, Sahashi Kentaro, Kondo Naohide, Nakatsuji Hideaki, Tohnai Genki, Katsuno Masahisa

    NEUROLOGY   Vol. 94 ( 15 )   2020.4

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  16. Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis

    Ito Daisuke, Hashizume Atsushi, Hijikata Yasuhiro, Yamada Shinichiro, Iguchi Yohei, Iida Madoka, Kishimoto Yoshiyuki, Moriyoshi Hideyuki, Hirakawa Akihiro, Katsuno Masahisa

    JOURNAL OF NEUROLOGY   Vol. 266 ( 12 ) page: 2952 - 2961   2019.12

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    Objective: To assess the changes of muscle-related biomarkers at the early stage of amyotrophic lateral sclerosis, and to confirm these findings in an experimental animal model. Methods: Thirty-nine subjects with sporadic amyotrophic lateral sclerosis and 20 healthy controls were enrolled and longitudinally evaluated. We evaluated serum creatine kinase and creatinine levels and appendicular lean soft-tissue mass using dual X-ray absorptiometry. The levels of biomarkers at early ALS stages were estimated using linear mixed models with unstructured correlation and random intercepts. We also analyzed the longitudinal changes of serum creatine kinase and creatinine, together with the mRNA levels of acetylcholine receptor subunit γ (Chrng) and muscle-associated receptor tyrosine kinase, markers of denervation, in the gastrocnemius muscle of superoxide dismutase 1 (SOD1)G93A transgenic mice, an animal model of amyotrophic lateral sclerosis. Results: The estimated levels of creatine kinase were higher in subjects with amyotrophic lateral sclerosis at the early stage than in healthy controls, although the estimated appendicular lean soft-tissue mass and creatinine levels were equivalent between both groups, suggesting that the elevation of creatine kinase precedes both muscular atrophy and subjective motor symptoms in sporadic amyotrophic lateral sclerosis. In SOD1G93A mice, the serum levels of creatine kinase were elevated at 9 weeks of age (peri-onset) when Chrng started to be up-regulated, and were then down-regulated at 15 weeks of age, consistent with the clinical data from patients with sporadic amyotrophic lateral sclerosis. Interpretation: Creatine kinase elevation precedes muscular atrophy and reflects muscle denervation at the early stage.

    DOI: 10.1007/s00415-019-09507-6

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  17. Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy Reviewed

    Iida Madoka, Sahashi Kentaro, Kondo Naohide, Nakatsuji Hideaki, Tohnai Genki, Tsutsumi Yutaka, Noda Seiya, Murakami Ayuka, Onodera Kazunari, Okada Yohei, Nakatochi Masahiro, Okabe Yuka Tsukagoshi, Shimizu Shinobu, Mizuno Masaaki, Adachi Hiroaki, Okano Hideyuki, Sobue Gen, Katsuno Masahisa

    NATURE COMMUNICATIONS   Vol. 10 ( 1 ) page: 4262   2019.9

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    Authorship:Lead author   Language:Japanese   Publisher:Nature Communications  

    © 2019, The Author(s). Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.

    DOI: 10.1038/s41467-019-12282-7

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  18. DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5

    Kondo Naohide, Tohnai Genki, Sahashi Kentaro, Iida Madoka, Kataoka Mayumi, Nakatsuji Hideaki, Tsutsumi Yutaka, Hashizume Atsushi, Adachi Hiroaki, Koike Haruki, Shinjo Keiko, Kondo Yutaka, Sobue Gen, Katsuno Masahisa

    EMBO MOLECULAR MEDICINE   Vol. 11 ( 5 )   2019.5

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    Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG-rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper-methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over-expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper-methylation underlies the neurodegeneration in SBMA.

    DOI: 10.15252/emmm.201708547

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  19. Akt signaling pathway is dysregulated in polyglutamine diseases

    Iida M., Sahashi K., Kondo N., Nakatsuji H., Tohnai G., Tsutsumi Y., Adachi H., Sobue G., Katsuno M.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 209 - 209   2017.10

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    DOI: 10.1016/j.jns.2017.08.597

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  20. Understanding of the role of proteinaceous inclusions in spinal and bulbar muscular atrophy

    Sahashi K., Kondo N., Iida M., Nakatsuji H., Tohnai G., Iguchi Y., Sobue G., Katsuno M.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 709 - 709   2017.10

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  21. DNA methylation inhibitor mitigates spinal and bulbar muscular atrophy model mouse

    Kondo N., Sahashi K., Iida M., Nakatsuji H., Tohnai G., Adachi H., Sobue G., Katsuno M.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 476 - 477   2017.10

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  22. Therapeutic strategies for spinal and bulbar muscular atrophy

    Kondo Naohide, Sahashi Kentaro, Iida Madoka, Tohnai Genki, Sobue Gen, Katsuno Masahisa

    Neurological Therapeutics   Vol. 34 ( 2 ) page: 101 - 106   2017

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    Language:Japanese   Publisher:Japanese Society of Neurological Therapeutics  

    <p>Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is an adult–onset neuromuscular disease caused by an expansion of a CAG triplet–repeat within the first exon of the androgen receptor gene. Recent studies have indicated that SBMA is not a pure neurodegenerative disease, but affecting various non–neuronal tissues, including skeletal muscle. Furthermore, impairment in the interaction between motor neurons and skeletal muscles may be the key mechanism underlying the pathophysiology of SBMA. In the presence of testosterone, a disease–causing abnormal AR protein accumulates in the brainstem, spinal anterior horn, skeletal muscle, and several peripheral organs ; this induces a variety of symptoms, such as bulbar and muscular atrophy, liver dysfunction, and arrhythmia, in patients with SBMA. Studies using animal models have resulted in the development of promising therapeutic strategies for SBMA, including 1) testosterone suppression, 2) mutant androgen receptor gene silencing, 3) activation of protein quality control, and 4) rescuing of mitochondrial function. Efficacy of physical therapy has also been tested in small–scale clinical trials. In this review, we describe the clinical features and pathogenesis of SBMA, and summarize the therapeutic drug targets developed on the basis of results from recent studies using the well–established mouse models for this neuromuscular disease. Strategies for the development of disease–modifying therapy supported by basic experiments as well as well–planned clinical trials may lead to a breakthrough in the therapy for SBMA.</p>

    DOI: 10.15082/jsnt.34.2_101

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Books 5

  1. 細胞のメカニズムと神経疾患 神経変性疾患におけるJNK

    飯田円、勝野雅央( Role: Joint author)

    中外医学社  2022 

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    Total pages:3   Responsible for pages:1193-1195   Language:Japanese Book type:Scholarly book

  2. 輝け次代の担い手たち、球脊髄性筋萎縮症におけるSrc病態

    飯田 円( Role: Joint author)

    神経化学  2021 

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    Total pages:8   Responsible for pages:1-8   Language:Japanese

  3. 「SBMAの病態はどこまでわかっていますか?」

    飯田円、近藤直英、佐橋健太郎、勝野雅央( Role: Joint author)

    中外医学社  2017 

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    Language:Japanese Book type:Textbook, survey, introduction

  4. 特集 運動ニューロン病、球脊髄性筋萎縮症の病態と治療法開発

    近藤直英、佐橋健太郎、飯田円、藤内玄規、祖父江元、勝野雅央( Role: Joint author)

    神経治療学  2017 

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    Total pages:6   Responsible for pages:101-106   Language:Japanese Book type:Textbook, survey, introduction

  5. 「球脊髄性筋萎縮症のdisease modifying therapy (DMT)」

    飯田円、勝野雅央( Role: Joint author)

    南江堂  2017 

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    Language:Japanese Book type:Textbook, survey, introduction

MISC 4

  1. Development of symptomatic therapy for cold paresis in spinal and bulbar muscular atrophy(和訳中)

    Yamada Shinichiro, Hashizume Atsushi, Hijikata Yasuhiro, Ito Daisuke, Kishimoto Yoshiyuki, Moriyoshi Hideyuki, Iida Madoka, Nakamura Tomohiko, Katsuno Masahisa

    臨床神経学   Vol. 59 ( Suppl. ) page: S395 - S395   2019.11

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    Language:English   Publisher:(一社)日本神経学会  

  2. 筋萎縮性側索硬化症発症時の血清クレアチンキナーゼ上昇(Elevation of serum creatine kinase at the onset of Amyotrophic Lateral Sclerosis)

    Ito Daisuke, Hashizume Atsushi, Hijikata Yasuhiro, Yamada Shinichiro, Inagaki Tomonori, Iguchi Yohei, Iida Madoka, Katsuno Masahisa

    臨床神経学   Vol. 58 ( Suppl. ) page: S383 - S383   2018.12

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    Language:English   Publisher:(一社)日本神経学会  

  3. 球脊髄性筋萎縮症における寒冷麻痺の病態生理(Pathophysiology of cold paresis in spinal and bulbar muscular atrophy)

    Yamada Shinichiro, Hashizume Atsushi, Hijikata Yasuhiro, Inagaki Tomonori, Ito Daisuke, Iida Madoka, Sahashi Kentaro, Fukaya Ryota, Nakamura Tomohiko, Kuba Hiroshi, Katsuno Masahisa

    臨床神経学   Vol. 58 ( Suppl. ) page: S416 - S416   2018.12

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    Language:English   Publisher:(一社)日本神経学会  

  4. 【運動ニューロン病】球脊髄性筋萎縮症の病態と治療法の開発

    近藤 直英, 佐橋 健太郎, 飯田 円, 藤内 玄規, 祖父江 元, 勝野 雅央

    神経治療学   Vol. 34 ( 2 ) page: 101 - 106   2017.3

Presentations 4

  1. 育児と留学とキャリア形成 Invited

    飯田 円

    名大ネットワークキャリアセミナーオンライン  2023.2.10  名大卒後臨床研修・キャリア形成支援センター

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    Event date: 2023.2

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:名大病院   Country:Japan  

  2. 女性研究者のキャリアと留学 Invited

    飯田 円

    2022年名大神経内科サマースクール  2022.8.20 

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    Event date: 2022.8

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Country:Japan  

  3. 脳神経内科医の働き方の1例 筋脊髄性筋萎縮症の病態解明に向けて Invited

    飯田 円

    第3回NIN研究会  2021.12.9  武田薬品工業株式会社

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    Event date: 2021.12

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Country:Japan  

  4. 筋脊髄性筋萎縮症の病態解明 Invited

    飯田 円

    第7回Nagoya Neurology Forum   2021.11.9  田辺三菱製薬株式会社

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    Event date: 2021.11

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Country:Japan  

Research Project for Joint Research, Competitive Funding, etc. 7

  1. 球脊髄性筋萎縮症におけるオリゴデンドロサイトによる神経変性基盤の解明

    2024.4

    堀科学芸術振興財団 研究助成事業 

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    Authorship:Principal investigator 

  2. シングルセル解析による球脊髄性筋萎縮症の病態解明

    2023.4

    SBMAの会  2023年度SBMAの会研究支援事業 

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    Authorship:Principal investigator  Grant type:Other

    Grant amount:\200000

  3. シングルセルRNA seq とATAC seq を用いた球脊髄性筋萎縮症の早期病態の解明

    2021.4

    公益財団法人 武田科学振興財団  2021年度医学系研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000

  4. 運動ニューロン疾患の発症機構をシングルセルテクノロジーを用いて解明する

    2021.4 - 2022.3

    一般財団法人共済団  令和3年度 医学研究奨励助成金 

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    Authorship:Principal investigator 

    Grant amount:\500000

  5. Srcシグナルを標的としたSBMAの治療法開発

    2018.4 - 2019.3

    SBMAの会  2018年度SBMAの会研究支援事業 

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    Authorship:Principal investigator  Grant type:Other

    Grant amount:\200000

  6. 運動ニューロン疾患の時空間的分子シグナル異常を標的とした治療法開発

    2015.4 - 2016.3

    かなえ医薬振興財団  かなえ医薬振興財団 研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1000000

  7. Spinal and bulbar muscular atrophy (SBMA)に対するPPAR gamma agonist (pioglitazone)の効果

    2012.4 - 2013.3

    平成24年度グローバルCOE研究者自立支援プログラム 

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    Authorship:Principal investigator  Grant type:Other

    Grant amount:\500000

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KAKENHI (Grants-in-Aid for Scientific Research) 5

  1. Elucidation of temporal alteration in motor neuron-oligodendrocyte interaction in motor neuron diseases

    Grant number:23H00420  2023.4 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

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    Authorship:Coinvestigator(s) 

  2. In silico解析を活用した球脊髄性筋萎縮症の骨格筋病態の解明

    Grant number:22K15705  2022.4 - 2024.3

    科学研究費助成事業  若手研究

    飯田 円

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    Authorship:Principal investigator 

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

  3. シングルセル解析による球脊髄性筋萎縮症の早期病態解明と治療法開発

    Grant number:21K20686  2021.8 - 2023.3

    科学研究費助成事業  研究活動スタート支援

    飯田 円

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    Authorship:Principal investigator 

    Grant amount:\3120000 ( Direct Cost: \2400000 、 Indirect Cost:\720000 )

  4. Molecular mechanisms of neurocircuit in motor neuron diseases

    Grant number:18K15361  2018.4 - 2020.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Iida Madoka

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, progressive neuromuscular disease caused by the expanded CAG repeats in the androgen receptor (AR) gene. We performed a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) and revealed thattThe level of phosphorylated Src (p-Src) was markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Src phosphorylation was also elevated in motor neurons and skeletal muscles of the patients with SBMA. We identified p130Cas as effector molecules of Src. We also revealed that the interaction between Src and AR plays an essential role in the activation of Src pathway in the pathogenesis of SBMA. Finally, the administration of compound X, a novel SKI, ameliorated the neurological phenotype of the mouse model of SBMA.

  5. 神経筋ネットワーク変性における分子シグナル異常を標的とした治療法開発

    Grant number:17J40128  2017.4 - 2020.3

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    飯田 円

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    A. 運動ニューロン疾患における時空間的分子シグナル異常の解明と治療法開発
    本年度は球脊髄性筋萎縮症(SBMA)の病態においてSrcが活性化する機序を解析した。まず野生型細胞株(NSC34、C2C12)とコントロール細胞モデル(AR-24Q)におけるSrcのリン酸化レベルを比較した。コントロール細胞モデルでは野生型細胞株よりもSrcのリン酸化が亢進しており、Srcの活性化にARの本来の機能が関与していることが示唆された。さらにARとSrcの結合部位を欠損させた「deleted ARプラスミド」もしくは「deleted Srcプラスミド」を細胞に一過性強制発現させることにより、ARとSrcの結合がSrcのリン酸化に与える影響を解析した。ARとSrcの結合が低下している細胞ではSrcのリン酸化が低下しており、Srcの活性化にはARとSrcの直接的な結合が重要であることが示された。本年度までに行った研究について「Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy」というタイトルでNature Communications誌に発表した(Iida et al. Nat Commun. 2019)。
    B. 下位運動ニューロンにおける神経回路障害の分子メカニズム
    下位運動ニューロンにおける神経回路障害の分子メカニズムの解明については、CAGリピートが97個に延長したヒトARをloxP配列で挟み、C末端にNanolucルシフェラーゼ配列をもつ全長約4.5kbpの人工遺伝子を完成さた。マウス受精卵にinjectionを行い、AR-floxマウス作成を試みている。

 

Teaching Experience (On-campus) 6

  1. 神経内科学

    2023

  2. 神経学

    2023

  3. 神経内科学

    2022

  4. Neurology

    2022

  5. 神経内科学

    2022

  6. ニューロサイエンスコース

    2022

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