研究者詳細 - 伊藤　美佳子

論文 - 伊藤　美佳子

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Meclozine ameliorates skeletal muscle pathology and increases muscle forces in<i> mdx</i> mice 査読有り国際誌 Open Access

Kawamura, Y; Hida, T; Ohkawara, B; Matsushita, M; Kobayashi, T; Ishizuka, S; Hiraiwa, H; Tanaka, S; Tsushima, M; Nakashima, H; Ito, K; Imagama, S; Ito, M; Masuda, A; Ishiguro, N; Ohno, K

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 592 巻頁： 87 - 92 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

We screened pre-approved drugs for the survival of the Hu5/KD3 human myogenic progenitors. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, promoted the proliferation and survival of Hu5/KD3 cells. Meclozine increased expression of MyoD, but reduced expression of myosin heavy chain and suppressed myotube formation. Withdrawal of meclozine, however, resumed the ability of Hu5/KD3 cells to differentiate into myotubes. We examined the effects of meclozine on mdx mouse carrying a nonsense mutation in the dystrophin gene and modeling for Duchenne muscular dystrophy. Intragastric administration of meclozine in mdx mouse increased the body weight, the muscle mass in the lower limbs, the cross-sectional area of the paravertebral muscle, and improved exercise performances. Previous reports show that inhibition of phosphorylation of ERK1/2 improves muscle functions in mouse models for Emery-Dreifuss muscular dystrophy and cancer cachexia, as well as in mdx mice. We and others previously showed that meclozine blocks the phosphorylation of ERK1/2 in cultured cells. We currently showed that meclozine decreased phosphorylation of ERK1/2 in muscles in mdx mice but not in wild-type mice. This was likely to be one of the underlying mechanisms of the effects of meclozine on mdx mice.

DOI： 10.1016/j.bbrc.2022.01.003

Altered gut microbiota in Parkinson's disease patients with motor complications 査読有り国際誌 Open Access

Takahashi, K; Nishiwaki, H; Ito, M; Iwaoka, K; Takahashi, K; Suzuki, Y; Taguchi, K; Yamahara, K; Tsuboi, Y; Kashihara, K; Hirayama, M; Ohno, K; Maeda, T

PARKINSONISM & RELATED DISORDERS 95 巻頁： 11 - 17 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Parkinsonism and Related Disorders

Introduction: Parkinson's disease (PD) is associated with gut dysbiosis. However, whether gut dysbiosis can cause motor complications is unclear. Methods: Subjects were enrolled from four independent movement disorder centers in Japan. We performed 16S ribosomal RNA gene sequence analysis of gut microbiota. Relative abundance of gut microbiota and relationships between them and clinical characteristics were statistically analyzed. Analysis of co-variance (ANCOVA) was used to assess altered gut microbiota associated with wearing-off or dyskinesia. Results: We enrolled 223 patients with PD. Wearing-off was noted in 47.5% of patients and dyskinesia in 21.9%. We detected 98 genera of bacteria. Some changes in the gut microbiota were observed in patients with PD and motor complications. After Bonferroni correction, patients with wearing-off showed decreased relative abundance of Lachnospiraceae Blautia (p < 0.0001) and increased relative abundance of Lactobacillaceae Lactobacillus (p < 0.0001), but patients with dyskinesia no longer showed significant changes in the gut microbiota. Adjustment with two models of confounding factors followed by ANCOVA revealed that age (p < 0.0001), disease duration (p = 0.01), and wearing-off (p = 0.0004) were independent risks for the decreased relative abundance of Lachnospiraceae Blautia, and wearing-off (p = 0.009) was the only independent risk factor for the increased relative abundance of Lachnospiraceae Lactobacillus. Conclusion: Relative abundance of Lachnospiraceae Blautia and Lactobacillaceae Lactobacillus was significantly decreased and increased, respectively, in the gut microbiota of PD patients with motor complications. This indicates that an altered gut microbiota is associated with the development of motor complications in patients with advanced PD.

DOI： 10.1016/j.parkreldis.2021.12.012

Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma 査読有り Open Access

Tanaka, H; Matsumura, S; Ishikawa, K; Hashizume, H; Ito, M; Nakamura, K; Kajiyama, H; Kikkawa, F; Ito, M; Ohno, K; Okazaki, Y; Toyokuni, S; Mizuno, M; Hori, M

JAPANESE JOURNAL OF APPLIED PHYSICS 61 巻 ( SA ) 2022年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Applied Physics

Ethanol production by budding yeast was compared between direct and indirect plasma irradiation. We observed enhancement of ethanol production and cell growth not by indirect plasma irradiation but by direct plasma irradiation. Glucose consumption was increased in budding yeast by direct plasma irradiation. Extracellular flux analysis revealed that glycolytic activity in the budding yeast was elevated by direct plasma irradiation. These results suggest that direct plasma irradiation enhances ethanol production in budding yeast by elevating the glycolytic activity.

DOI： 10.35848/1347-4065/ac2037

Intestinal <i>Collinsella</i> may mitigate infection and exacerbation of COVID-19 by producing ursodeoxycholate 査読有り国際誌 Open Access

Hirayama, M; Nishiwaki, H; Hamaguchi, T; Ito, M; Ueyama, J; Maeda, T; Kashihara, K; Tsuboi, Y; Ohno, K

PLOS ONE 16 巻 ( 11 ) 頁： e0260451 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

The mortality rates of COVID-19 vary widely across countries, but the underlying mechanisms remain unelucidated. We aimed at the elucidation of relationship between gut microbiota and the mortality rates of COVID-19 across countries. Raw sequencing data of 16S rRNA V3-V5 regions of gut microbiota in 953 healthy subjects in ten countries were obtained from the public database. We made a generalized linear model (GLM) to predict the COVID- 19 mortality rates using gut microbiota. GLM revealed that low genus Collinsella predicted high COVID-19 mortality rates with a markedly low p-value. Unsupervised clustering of gut microbiota in 953 subjects yielded five enterotypes. The mortality rates were increased from enterotypes 1 to 5, whereas the abundances of Collinsella were decreased from enterotypes 1 to 5 except for enterotype 2. Collinsella produces ursodeoxycholate. Ursodeoxycholate was previously reported to inhibit binding of SARS-CoV-2 to angiotensin-converting enzyme 2; suppress pro-inflammatory cytokines like TNF-α, IL-1β, IL-2, IL-4, and IL-6; have antioxidant and anti-apoptotic effects; and increase alveolar fluid clearance in acute respiratory distress syndrome. Ursodeoxycholate produced by Collinsella may prevent COVID-19 infection and ameliorate acute respiratory distress syndrome in COVID-19 by suppressing cytokine storm syndrome.

DOI： 10.1371/journal.pone.0260451

Regulated splicing of large exons is linked to phase-separation of vertebrate transcription factors 査読有り国際誌 Open Access

Kawachi, T; Masuda, A; Yamashita, Y; Takeda, J; Ohkawara, B; Ito, M; Ohno, K

EMBO JOURNAL 40 巻 ( 22 ) 頁： e107485 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：EMBO Journal

Although large exons cannot be readily recognized by the spliceosome, many are evolutionarily conserved and constitutively spliced for inclusion in the processed transcript. Furthermore, whether large exons may be enriched in a certain subset of proteins, or mediate specific functions, has remained unclear. Here, we identify a set of nearly 3,000 SRSF3-dependent large constitutive exons (S3-LCEs) in human and mouse cells. These exons are enriched for cytidine-rich sequence motifs, which bind and recruit the splicing factors hnRNP K and SRSF3. We find that hnRNP K suppresses S3-LCE splicing, an effect that is mitigated by SRSF3 to thus achieve constitutive splicing of S3-LCEs. S3-LCEs are enriched in genes for components of transcription machineries, including mediator and BAF complexes, and frequently contain intrinsically disordered regions (IDRs). In a subset of analyzed S3-LCE-containing transcription factors, SRSF3 depletion leads to deletion of the IDRs due to S3-LCE exon skipping, thereby disrupting phase-separated assemblies of these factors. Cytidine enrichment in large exons introduces proline/serine codon bias in intrinsically disordered regions and appears to have been evolutionarily acquired in vertebrates. We propose that layered splicing regulation by hnRNP K and SRSF3 ensures proper phase-separation of these S3-LCE-containing transcription factors in vertebrates.

DOI： 10.15252/embj.2020107485

Plasma-activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells 査読有り

Tanaka, H; Maeda, S; Nakamura, K; Hashizume, H; Ishikawa, K; Ito, M; Ohno, K; Mizuno, M; Motooka, Y; Okazaki, Y; Toyokuni, S; Kajiyama, H; Kikkawa, F; Hori, M

PLASMA PROCESSES AND POLYMERS 18 巻 ( 10 ) 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Plasma Processes and Polymers

Nonequilibrium atmospheric pressure plasma has enabled a variety of new applications in medicine, agriculture, and other industries. It is particularly noteworthy that plasma itself and/or plasma-activated culture medium have been shown to preferentially kill various cancer cells. We have previously developed a plasma-activated Ringer's lactate solution (PAL) for use as a new cancer treatment. In this study, behaviors of extracellular and intracellular reactive oxygen and nitrogen species in the cellular respiratory system of PAL-treated HeLa cells were investigated using an extracellular flux analyzer and a probe to measure mitochondrial membrane potential. In PAL-treated HeLa cells, extracellular hydrogen peroxide in PAL was found to be responsible for the induction of intracellular hydrogen peroxide and apoptosis, while other components in PAL are responsible for the induction of non-H2O2 intracellular ROS and non-apoptotic cell death, which should be clarified by further experiments. We believe that these are long-lived species derived from plasma-activated lactates. Furthermore, we found that the plasma-activated lactates inhibited glycolysis and the tricarboxylic acid (TCA) cycle, but not the electron transport chain in HeLa cells. These results suggest that PAL induces multiple modes of cell death, including apoptosis through hydrogen peroxide, and non-apoptotic cell death associated with the impairment of mitochondrial functions (glycolysis and TCA cycle). These findings shed light on the novel mechanism underlying plasma-activated lactate-induced cell death.

DOI： 10.1002/ppap.202100056

Zonisamide upregulates neuregulin-1 expression and enhances acetylcholine receptor clustering at the in vitro neuromuscular junction 査読有り国際誌

Inoue, T; Ohkawara, B; Bushra, S; Kanbara, S; Nakashima, H; Koshimizu, H; Tomita, H; Ito, M; Masuda, A; Ishiguro, N; Imagama, S; Ohno, K

NEUROPHARMACOLOGY 195 巻頁： 108637 - 108637 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neuropharmacology

Decreased acetylcholine receptor (AChR) clustering compromises signal transmission at the neuromuscular junction (NMJ) in myasthenia gravis, congenital myasthenic syndromes, and motor neuron diseases. Although the enhancement of AChR clustering at the NMJ is a promising therapeutic strategy for these maladies, no drug is currently available for this enhancement. We previously reported that zonisamide (ZNS), an anti-epileptic and anti-Parkinson's disease drug, enhances neurite elongation of the primary spinal motor neurons (SMNs). As nerve sprouting occurs to compensate for the loss of AChR clusters in human diseases, we examined the effects of ZNS on AChR clustering at the NMJ. To this end, we established a simple and quick co-culture system to reproducibly make in vitro NMJs using C2C12 myotubes and NSC34 motor neurons. ZNS at 1–20 μM enhanced the formation of AChR clusters dose-dependently in co-cultured C2C12 myotubes but not in agrin-treated single cultured C2C12 myotubes. We observed that molecules that conferred responsiveness to ZNS were not secreted into the co-culture medium. We found that 10 μM ZNS upregulated the expression of neuregulin-1 (Nrg1) in co-cultured cells but not in single cultured C2C12 myotubes or single cultured NSC34 motor neurons. In accordance with this observation, inhibition of the Nrg1/ErbB signaling pathways nullified the effect of 10 μM ZNS on the enhancement of AChR clustering in in vitro NMJs. Although agrin was not induced by 10 μM ZNS in co-cultured cells, anti-agrin antibody attenuated ZNS-mediated enhancement of AChR clustering. We conclude that ZNS enhances agrin-dependent AChR-clustering by upregulating the Nrg1/ErbB signaling pathways in the presence of NMJs.

DOI： 10.1016/j.neuropharm.2021.108637

Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology 査読有り国際誌 Open Access

Ohkawara, B; Ito, M; Ohno, K

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 22 巻 ( 5 ) 頁： 1 - 16 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

Signal transduction at the neuromuscular junction (NMJ) is affected in many human dis-eases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton my-asthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-den-sity lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and con-nective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.

DOI： 10.3390/ijms22052455

Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model 査読有り

Koshimizu, H; Ohkawara, B; Nakashima, H; Ota, K; Kanbara, S; Inoue, T; Tomita, H; Sayo, A; Kiryu-Seo, S; Konishi, H; Ito, M; Masuda, A; Ishiguro, N; Imagama, S; Kiyama, H; Ohno, K

LIFE SCIENCES 263 巻頁： 118577 - 118577 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.

DOI： 10.1016/j.lfs.2020.118577

A set of random forest models for each amino acid substitution to predict pathogenicity of missense variants in the human genome

Takeda J., Nanatsue K., Yamagishi R., Ito M., Ohno K.

EUROPEAN JOURNAL OF HUMAN GENETICS 28 巻 ( SUPPL 1 ) 頁： 1003 - 1003 2020年12月

A set of random forest models for each amino acid substitution to predict pathogenicity of missense variants in the human genome 査読有り

Takeda J., Nanatsue K., Yamagishi R., Ito M., Ohno K.

EUROPEAN JOURNAL OF HUMAN GENETICS 28 巻 ( SUPPL 1 ) 頁： 1003 - 1003 2020年12月

Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson's Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder 査読有り国際誌 Open Access

Nishiwaki, H; Hamaguchi, T; Ito, M; Ishida, T; Maeda, T; Kashihara, K; Tsuboi, Y; Ueyama, J; Shimamura, T; Mori, H; Kurokawa, K; Katsuno, M; Hirayama, M; Ohnoa, K

MSYSTEMS 5 巻 ( 6 ) 頁： e00797-20 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：mSystems

Gut dysbiosis has been repeatedly reported in Parkinson's disease (PD) but only once in idiopathic rapid-eye-movement sleep behavior disorder (iRBD) from Germany. Abnormal aggregation of a-synuclein fibrils causing PD possibly starts from the intestine, although this is still currently under debate. iRBD patients frequently develop PD. Early-stage gut dysbiosis that is causally associated with PD is thus expected to be observed in iRBD. We analyzed gut microbiota in 26 iRBD patients and 137 controls by 16S rRNA sequencing (16S rRNA-seq). Our iRBD data set was meta-analyzed with the German iRBD data set and was compared with gut microbiota in 223 PD patients. Unsupervised clustering of gut microbiota by LIGER, a topic model-based tool for single-cell RNA sequencing (RNA-seq) analysis, revealed four enterotypes in controls, iRBD, and PD. Short-chain fatty acid (SCFA)-producing bacteria were conserved in an enterotype observed in controls and iRBD, whereas they were less conserved in enterotypes observed in PD. Genus Akkermansia and family Akkermansiaceae were consistently increased in both iRBD in two countries and PD in five countries. Short-chain fatty acid (SCFA)-producing bacteria were not significantly decreased in iRBD in two countries. In contrast, we previously reported that recognized or putative SCFA-producing genera Faecalibacterium, Roseburia, and Lachnospiraceae ND3007 group were consistently decreased in PD in five countries. In a-synucleinopathy, increase of mucin-layer-degrading genus Akkermansia is observed at the stage of iRBD, whereas decrease of SCFA-producing genera becomes obvious with development of PD. IMPORTANCE Twenty studies on gut microbiota in PD have been reported, whereas only one study has been reported on iRBD from Germany. iRBD has the highest likelihood ratio to develop PD. Our meta-analysis of iRBD in Japan and Germany revealed increased mucin-layer-degrading genus Akkermansia in iRBD. Genus Akkermansia may increase the intestinal permeability, as we previously observed in PD patients, and may make the intestinal neural plexus exposed to oxidative stress, which can lead to abnormal aggregation of prion-like a-synuclein fibrils in the intestine. In contrast to PD, SCFA-producing bacteria were not decreased in iRBD. As SCFA induces regulatory T (Treg) cells, a decrease of SCFA-producing bacteria may be a prerequisite for the development of PD. We propose that prebiotic and/or probiotic therapeutic strategies to increase the intestinal mucin layer and to increase intestinal SCFA potentially retard the development of iRBD and PD.

DOI： 10.1128/mSystems.00797-20

Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage 国際誌 Open Access

Takeuchi, A; Takahashi, Y; Iida, K; Hosokawa, M; Irie, K; Ito, M; Brown, JB; Ohno, K; Nakashima, K; Hagiwara, M

STEM CELL REPORTS 15 巻 ( 4 ) 頁： 883 - 897 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Stem Cell Reports

During brain development, neural stem cells (NSCs) initially produce neurons and change their fate to generate glias. While the regulation of neurogenesis is well characterized, specific markers for glial precursor cells (GPCs) and the master regulators for gliogenesis remain unidentified. Accumulating evidence suggests that RNA-binding proteins (RBPs) have significant roles in neuronal development and function, as they comprehensively regulate the expression of target genes in a cell-type-specific manner. We systematically investigated the expression profiles of 1,436 murine RBPs in the developing mouse brain and identified quaking (Qk) as a marker of the putative GPC population. Functional analysis of the NSC-specific Qk-null mutant mouse revealed the key role of Qk in astrocyte and oligodendrocyte generation and differentiation from NSCs. Mechanistically, Qk upregulates gliogenic genes via quaking response elements in their 3′ untranslated regions. These results provide crucial directions for identifying GPCs and deciphering the regulatory mechanisms of gliogenesis from NSCs.

DOI： 10.1016/j.stemcr.2020.08.010

Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle 国際誌 Open Access

Huang, K; Li, J; Ito, M; Takeda, JI; Ohkawara, B; Ogi, T; Masuda, A; Ohno, K

FRONTIERS IN MOLECULAR NEUROSCIENCE 13 巻頁： 154 - 154 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Molecular Neuroscience

The neuromuscular junction (NMJ) is a prototypic chemical synapse between the spinal motor neuron and the motor endplate. Gene expression profiles of the motor endplate are not fully elucidated. Collagen Q (ColQ) is a collagenic tail subunit of asymmetric forms of acetylcholinesterase and is driven by two distinct promoters. pColQ1 is active throughout the slow-twitch muscle, whereas pColQ1a is active at the motor endplate of fast-twitch muscle. We made a transgenic mouse line that expresses nuclear localization signal (NLS)-attached Cre recombinase under the control of pColQ1a (pColQ1a-Cre mouse). RiboTag mouse expresses an HA-tagged ribosomal subunit, RPL22, in cells expressing Cre recombinase. We generated pColQ1a-Cre:RiboTag mouse, and confirmed that HA-tagged RPL22 was enriched at the NMJ of tibialis anterior (TA) muscle. Next, we confirmed that Chrne and Musk that are specifically expressed at the NMJ were indeed enriched in HA-immunoprecipitated (IP) RNA, whereas Sox10 and S100b, markers for Schwann cells, and Icam1, a marker for vascular endothelial cells, and Pax3, a marker for muscle satellite cells, were scarcely detected. Gene set enrichment analysis (GSEA) of RNA-seq data showed that “phosphatidylinositol signaling system” and “extracellular matrix receptor interaction” were enriched at the motor endplate. Subsequent analysis revealed that genes encoding diacylglycerol kinases, phosphatidylinositol kinases, phospholipases, integrins, and laminins were enriched at the motor endplate. We first characterized the gene expression profile under translation at the motor endplate of TA muscle using the RiboTag technique. We expect that our gene expression profiling will help elucidate molecular mechanisms of the development, maintenance, and pathology of the NMJ.

DOI： 10.3389/fnmol.2020.00154

Meta-Analysisof Gut Dysbiosis in Parkinson's Disease 国際誌 Open Access

Nishiwaki, H; Ito, M; Ishida, T; Hamaguchi, T; Maeda, T; Kashihara, K; Tsuboi, Y; Ueyama, J; Shimamura, T; Mori, H; Kurokawa, K; Katsuno, M; Hirayama, M; Ohno, K

MOVEMENT DISORDERS 35 巻 ( 9 ) 頁： 1626 - 1635 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Movement Disorders

Background: PD may begin with the intestinal accumulation of α-synuclein fibrils, which can be causally associated with gut dysbiosis. The variability of gut microbiota across countries prevented us from identifying shared gut dysbiosis in PD. Objectives: To identify gut dysbiosis in PD across countries. Methods: We performed 16S ribosomal RNA gene sequencing analysis of gut microbiota in 223 patients with PD and 137 controls, and meta-analyzed gut dysbiosis by combining our dataset with four previously reported data sets from the United States, Finland, Russia, and Germany. We excluded uncommon taxa from our analyses. For pathway analysis, we developed the Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis method. Results: After adjusting for confounding factors (body mass index, constipation, sex, age, and catechol-O-methyl transferase inhibitor), genera Akkermansia and Catabacter, as well as families Akkermansiaceae, were increased, whereas genera Roseburia, Faecalibacterium, and Lachnospiraceae ND3007 group were decreased in PD. Catechol-O-methyl transferase inhibitor intake markedly increased family Lactobacillaceae. Inspection of these bacteria in 12 datasets that were not included in the meta-analysis revealed that increased genus Akkermansia and decreased genera Roseburia and Faecalibacterium were frequently observed across countries. Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis revealed changes in short-chain fatty acid metabolisms in our dataset. Conclusions: We report that intestinal mucin layer-degrading Akkermansia is increased and that short-chain fatty acid–producing Roseburia and Faecalibacterium are decreased in PD across countries. © 2020 International Parkinson and Movement Disorder Society.

DOI： 10.1002/mds.28119

CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction 査読有り国際誌 Open Access

Ohkawara, B; Kobayakawa, A; Kanbara, S; Hattori, T; Kubota, S; Ito, M; Masuda, A; Takigawa, M; Lyons, KM; Ishiguro, N; Ohno, K

EMBO REPORTS 21 巻 ( 8 ) 頁： e48462 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：EMBO Reports

At the neuromuscular junction (NMJ), lipoprotein-related receptor 4 (LRP4) mediates agrin-induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Here, we show that the CT domain of connective tissue growth factor (CTGF/CCN2) directly binds to the third beta-propeller domain of LRP4. CTGF/CCN2 enhances the binding of LRP4 to MuSK and facilitates the localization of LRP4 on the plasma membrane. CTGF/CCN2 enhances agrin-induced MuSK phosphorylation and AChR clustering in cultured myotubes. Ctgf-deficient mouse embryos (Ctgf−/−) have small AChR clusters and abnormal dispersion of synaptic vesicles along the motor axon. Ultrastructurally, the presynaptic nerve terminals have reduced numbers of active zones and mitochondria. Functionally, Ctgf−/− embryos exhibit impaired NMJ signal transmission. These results indicate that CTGF/CCN2 interacts with LRP4 to facilitate clustering of AChRs at the motor endplate and the maturation of the nerve terminal.

DOI： 10.15252/embr.201948462

Zonisamide ameliorates progression of cervical spondylotic myelopathy in a rat model 国際誌 Open Access

Kanbara, S; Ohkawara, B; Nakashima, H; Ohta, K; Koshimizu, H; Inoue, T; Tomita, H; Ito, M; Masuda, A; Ishiguro, N; Imagama, S; Ohno, K

SCIENTIFIC REPORTS 10 巻 ( 1 ) 頁： 13138 - 13138 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Cervical spondylotic myelopathy (CSM) is caused by chronic compression of the spinal cord and is the most common cause of myelopathy in adults. No drug is currently available to mitigate CSM. Herein, we made a rat model of CSM by epidurally implanting an expanding water-absorbent polymer underneath the laminae compress the spinal cord. The CSM rats exhibited progressive motor impairments recapitulating human CSM. CSM rats had loss of spinal motor neurons, and increased lipid peroxidation in the spinal cord. Zonisamide (ZNS) is clinically used for epilepsy and Parkinson's disease. We previously reported that ZNS protected primary spinal motor neurons against oxidative stress. We thus examined the effects of ZNS on our rat CSM model. CSM rats with daily intragastric administration of 0.5% methylcellulose (n = 11) and ZNS (30 mg/kg/day) in 0.5% methylcellulose (n = 11). Oral administration of ZNS ameliorated the progression of motor impairments, spared the number of spinal motor neurons, and preserved myelination of the pyramidal tracts. In addition, ZNS increased gene expressions of cystine/glutamate exchange transporter (xCT) and metallothionein 2A in the spinal cord in CSM rats, and also in the primary astrocytes. ZNS increased the glutathione (GSH) level in the spinal motor neurons of CSM rats. ZNS potentially ameliorates loss of the spinal motor neurons and demyelination of the pyramidal tracts in patients with CSM.

DOI： 10.1038/s41598-020-70068-0

InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution 査読有り Open Access

Takeda, J; Nanatsue, K; Yamagishi, R; Ito, M; Haga, N; Hirata, H; Ogi, T; Ohno, K

NAR GENOMICS AND BIOINFORMATICS 2 巻 ( 2 ) 頁： lqaa038 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NAR Genomics and Bioinformatics

In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision–recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

DOI： 10.1093/nargab/lqaa038

tRIP-seq reveals repression of premature polyadenylation by co-transcriptional FUS-U1 snRNP assembly 査読有り国際誌 Open Access

Masuda, A; Kawachi, T; Takeda, J; Ohkawara, B; Ito, M; Ohno, K

EMBO REPORTS 21 巻 ( 5 ) 頁： e49890 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：EMBO Reports

RNA processing occurs co-transcriptionally through the dynamic recruitment of RNA processing factors to RNA polymerase II (RNAPII). However, transcriptome-wide identification of protein–RNA interactions specifically assembled on transcribing RNAPII is challenging. Here, we develop the targeted RNA immunoprecipitation sequencing (tRIP-seq) method that detects protein–RNA interaction sites in thousands of cells. The high sensitivity of tRIP-seq enables identification of protein–RNA interactions at functional subcellular levels. Application of tRIP-seq to the FUS-RNA complex in the RNAPII machinery reveals that FUS binds upstream of alternative polyadenylation (APA) sites of nascent RNA bound to RNAPII, which retards RNAPII and suppresses the recognition of the polyadenylation signal by CPSF. Further tRIP-seq analyses demonstrate that the repression of APA is achieved by a complex composed of FUS and U1 snRNP on RNAPII, but not by either one alone. Moreover, our analysis reveals that FUS mutations in familial amyotrophic lateral sclerosis (ALS) that impair the FUS-U1 snRNP interaction aberrantly activate the APA sites. tRIP-seq provides new insights into the regulatory mechanism of co-transcriptional RNA processing by RNA processing factors.

DOI： 10.15252/embr.201949890

tRIP-seq reveals repression of premature polyadenylation by co-transcriptional FUS-U1 snRNP assembly

Masuda Akio, Kawachi Toshihiko, Takeda Jun-ichi, Ohkawara Bisei, Ito Mikako, Ohno Kinji

EMBO REPORTS 21 巻 ( 5 ) 頁： . 2020年5月

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