Updated on 2021/07/08

写真a

 
IGUCHI Yohei
 
Organization
Nagoya University Hospital Neurology Assistant Professor
Graduate School
Graduate School of Medicine
Title
Assistant Professor

Degree 1

  1. 博士(医学) ( 2010.3   名古屋大学 ) 

Research Interests 5

  1. Neuroscience

  2. Neurodegeneration

  3. Chemistry

  4. Biology

  5. Amyotrophic Lateral Sclerosis

Research Areas 1

  1. Life Science / Neurology

Research History 7

  1. 名古屋大学医学部附属病院   脳神経内科   助教

    2018.4

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    Country:Japan

  2. 名古屋大学医学部附属病院   神経内科   医員

    2016.8 - 2018.3

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    Country:Japan

  3. Laval University

    2013.6 - 2016.6

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    Country:Japan

  4. 名古屋大学大学院医学系研究科   神経内科   客員研究員

    2010.4 - 2013.6

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    Country:Japan

  5. 名古屋大学大学院医学系研究科   神経内科   大学院生(博士課程)

    2006.4 - 2010.3

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    Country:Japan

  6. 名古屋第一赤十字病院   神経内科   医員

    2003.4 - 2006.3

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    Country:Japan

  7. 名古屋第一赤十字病院   初期研修医

    2001.4 - 2003.3

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    Country:Japan

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Education 1

  1. Nagoya University   Graduate School, Division of Medical Sciences

    2006.4 - 2010.3

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    Country: Japan

Professional Memberships 6

  1. 日本神経学会

  2. 日本内科学会

  3. 日本神経科学会

  4. THE JAPAN NEUROSCIENCE SOCIETY

  5. JAPANESE SOCIETY OF NEUROLOGY

  6. THE JAPANESE SOCIETY OF INTERNAL MEDICINE

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Papers 13

  1. Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

    Riku Yuichi, Seilhean Danielle, Duyckaerts Charles, Boluda Susana, Iguchi Yohei, Ishigaki Shinsuke, Iwasaki Yasushi, Yoshida Mari, Sobue Gen, Katsuno Masahisa

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   Vol. 22 ( 8 )   2021.4

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    Language:Japanese   Publisher:International Journal of Molecular Sciences  

    Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations.

    DOI: 10.3390/ijms22083843

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  2. The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy

    Ando Takashi, Nakamura Ryoichi, Kuru Satoshi, Yokoi Daichi, Atsuta Naoki, Koike Haruki, Suzuki Masashi, Hara Kazuhiro, Iguchi Yohei, Harada Yumiko, Yoshida Yusuke, Hattori Makoto, Murakami Ayuka, Noda Seiya, Kimura Seigo, Sone Jun, Nakamura Tomohiko, Goto Yoji, Mano Kazuo, Okada Hisashi, Okuda Satoshi, Nishino Ichizo, Ogi Tomoo, Sobue Gen, Katsuno Masahisa

    NEUROBIOLOGY OF AGING   Vol. 100   page: 120.e1 - 120.e6   2021.4

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    Language:Japanese   Publisher:Neurobiology of Aging  

    Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35–58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be “deleterious” or “disease causing” using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.

    DOI: 10.1016/j.neurobiolaging.2020.10.028

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  3. Aggresome formation and liquid-liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43

    Watanabe Seiji, Inami Hidekazu, Oiwa Kotaro, Murata Yuri, Sakai Shohei, Komine Okiru, Sobue Akira, Iguchi Yohei, Katsuno Masahisa, Yamanaka Koji

    CELL DEATH & DISEASE   Vol. 11 ( 10 ) page: 909   2020.10

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    Language:Japanese   Publisher:Cell Death and Disease  

    Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid–liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS. To identify intracellular mechanisms responsible for TDP-43 aggregation, we established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes, and performed a screening. We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms, such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology. Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS) are involved in inducing the TDP-43 pathologies.

    DOI: 10.1038/s41419-020-03116-2

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  4. Exploring the factors underlying remyelination arrest by studying the post-transcriptional regulatory mechanisms of cystatin F gene

    Li Jiayi, Durose Wilaiwan Wisessmith, Ito Junko, Kakita Akiyoshi, Iguchi Yohei, Katsuno Masahisa, Kunisawa Kazuo, Shimizu Takeshi, Ikenaka Kazuhiro

    JOURNAL OF NEUROCHEMISTRY     2020.10

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    Language:Japanese   Publisher:Journal of Neurochemistry  

    Remyelination plays an important role in determining the fate of demyelinating disorders. However, it is arrested during chronic disease states. Cystatin F, a papain-like lysosomal cysteine proteinase inhibitor, is a crucial regulator of demyelination and remyelination. Using hemizygous proteolipid protein transgenic 4e (PLP4e/-) mice, an animal model of chronic demyelination, we found that cystatin F mRNA expression was induced at 2.5 months of age and up-regulated in the early phase of demyelination, but significantly decreased in the chronic phase. We next investigated cystatin F regulatory factors as potential mechanisms of remyelination arrest in chronic demyelinating disorders. We used the CysF-STOP-tetO::Iba-mtTA mouse model, in which cystatin F gene expression is driven by the tetracycline operator. Interestingly, we found that forced cystatin F mRNA over-expression was eventually decreased. Our findings show that cystatin F expression is modulated post-transcriptionally. We next identified embryonic lethal, abnormal vision, drosophila like RNA-binding protein 1 (ELAVL-1), and miR29a as cystatin F mRNA stabilizing and destabilizing factors, respectively. These roles were confirmed in vitro in NIH3T3 cells. Using postmortem plaque samples from human multiple sclerosis patients, we also confirmed that ELAVL-1 expression was highly correlated with the previously reported expression pattern of cystatin F. These data indicate the important roles of ELAVL-1 and miR29a in regulating cystatin F expression. Furthermore, they provide new insights into potential therapeutic targets for demyelinating disorders. (Figure presented.).

    DOI: 10.1111/jnc.15190

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  5. Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer

    Kanda Mitsuro, Shimizu Dai, Sawaki Koichi, Nakamura Shunsuke, Umeda Shinichi, Miwa Takashi, Tanaka Haruyoshi, Tanaka Chie, Hayashi Masamichi, Iguchi Yohei, Yamada Suguru, Katsuno Masahisa, Kodera Yasuhiro

    MOLECULAR CANCER   Vol. 19 ( 1 ) page: 131   2020.8

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    Language:Japanese   Publisher:Molecular Cancer  

    Background: Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods: Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr -/- mice, and assessed the clinical significance of NPTXR expression in GC specimens. Results: NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr -/- mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions: NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.

    DOI: 10.1186/s12943-020-01251-0

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  6. NUS1 mutation in a family with epilepsy, cerebellar ataxia, and tremor

    Araki Kunihiko, Nakamura Ryoichi, Ito Daisuke, Kato Kohji, Iguchi Yohei, Sahashi Kentaro, Toyama Miho, Hamada Kensuke, Okamoto Nobuhiko, Wada Yoshinao, Nakamura Tomohiko, Ogi Tomoo, Katsuno Masahisa

    EPILEPSY RESEARCH   Vol. 164   page: 106371   2020.8

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    Language:Japanese   Publisher:Epilepsy Research  

    We report on familial 5 epilepsy patients with autosomal dominant inheritance of a novel heterozygous NUS1 frameshift mutation. All patients had cerebellar ataxia and tremor. Three patients were diagnosed with childhood absence epilepsy, 1 patient with generalized epilepsy, and 1 patient with parkinsonism without epilepsy. Our cases and previously reported cases with deletions of chromosome 6q22 that include NUS1 share these common symptoms. In a cellular experiment, NUS1 mutation led to a substantial reduction of the protein level of NUS1. NUS1 mutation could contribute to epilepsy pathogenesis and also constitute a distinct syndromic entity with cerebellar ataxia and tremor.

    DOI: 10.1016/j.eplepsyres.2020.106371

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  7. Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis. Reviewed International journal

    Kensuke Ikenaka, Shinsuke Ishigaki, Yohei Iguchi, Kaori Kawai, Yusuke Fujioka, Satoshi Yokoi, Rehab F Abdelhamid, Seiichi Nagano, Hideki Mochizuki, Masahisa Katsuno, Gen Sobue

    Journal of neuropathology and experimental neurology   Vol. 79 ( 4 ) page: 370 - 377   2020.4

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    Alterations of RNA metabolism caused by mutations in RNA-binding protein genes, such as transactivating DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Unlike the accumulation of TDP43, which is accepted as a pathological hall mark of sporadic ALS (sALS), FUS pathology in sALS is still under debate. Although immunoreactive inclusions of FUS have been detected in sALS patients previously, the technical limitation of signal detection, including the necessity of specific antigen retrieval, restricts our understanding of FUS-associated ALS pathology. In this study, we applied a novel detection method using a conventional antigen retrieval technique with Sudan Black B treatment to identify FUS-positive inclusions in sALS patients. We classified pathological motor neurons into 5 different categories according to the different aggregation characteristics of FUS and TDP-43. Although the granular type was more dominant for inclusions with TDP-43, the skein-like type was more often observed in FUS-positive inclusions, suggesting that these 2 proteins undergo independent aggregation processes. Moreover, neurons harboring FUS-positive inclusions demonstrated substantially reduced expression levels of dynactin-1, a retrograde motor protein, indicating that perturbation of nucleocytoplasmic transport is associated with the formation of cytoplasmic inclusions of FUS in sALS.

    DOI: 10.1093/jnen/nlaa003

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

    Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M

    Journal of neurology   Vol. 266 ( 12 ) page: 2952 - 2961   2019.12

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  9. TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. Reviewed International journal

    Kunihiko Araki, Amane Araki, Daiyu Honda, Takako Izumoto, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Akitoshi Hara, Kazuhiro Ikumi, Kaori Kawai, Shinsuke Ishigaki, Yoko Nakamichi, Shin Tsunekawa, Yusuke Seino, Akiko Yamamoto, Yasunori Takayama, Shihomi Hidaka, Makoto Tominaga, Mica Ohara-Imaizumi, Atsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin-Ichi Muramatsu, Gen Sobue, Masahisa Katsuno

    The Journal of clinical investigation   Vol. 129 ( 9 ) page: 3578 - 3593   2019.9

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    TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

    DOI: 10.1172/JCI124481

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  10. Preclinical progression of neurodegenerative diseases

    Katsuno Masahisa, Sahashi Kentaro, Iguchi Yohei, Hashizume Atsushi

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 80 ( 3 ) page: 289 - 298   2018.8

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    DOI: 10.18999/nagjms.80.3.289

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  11. 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

  12. The role of TDP-43 secretion in association with exosomes

    Iguchi Y., Eid L., Parent M., Riku Y., Kawai K., Yoshida M., Katsuno M., Sobue G., Julien J. P.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 208 - 209   2017.10

  13. Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes Reviewed

    Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa Katsuno, Gen Sobue

    CELL REPORTS   Vol. 18 ( 5 ) page: 1118 - 1131   2017.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.

    DOI: 10.1016/j.celrep.2017.01.013

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Presentations 2

  1. TDP-43代謝におけるエクソソームの役割 International conference

    井口 洋平

    第59回日本神経学会学術大会  2018 

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    Language:English   Presentation type:Oral presentation (invited, special)  

  2. Emerging roles of exosomes in TDP-43 proteinopathy Invited International conference

    Yohei Iguchi

    PACTALS”and“Brain Protein Aging and Dementia Control”Project Joint Meeting  2017 

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    Language:English   Presentation type:Oral presentation (invited, special)  

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

  1. 孤発性ALSにおける凝集型TDP-43の生体内伝播メカニズムの解明

    Grant number:20H03589  2020.4 - 2023.3

    井口 洋平

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    Authorship:Principal investigator 

    Grant amount:\17680000 ( Direct Cost: \13600000 、 Indirect Cost:\4080000 )

    孤発性筋萎縮性側索硬化症において凝集型TDP-43がニューロン間をプリオンのように伝播することが想定されるが、実際に生体内でこのTDP-43のプリオン様伝播を証明した事例はない。研究代表者らはCre発現マウスとAAV-CMV-FLEXベクターを用いることによりTDP-43の生体内における細胞間伝播を強く示唆する結果を得ている。本研究では凝集型TDP-43の生体内伝播を”確実に”証明し、次にその伝播を修飾する因子を検討しsALSの病態抑止療法への展開を目指す。

  2. 超早期ライフステージに着目した神経変性疾患の時空間特異性の解明

    Grant number:20H00527  2020.4 - 2023.3

    勝野 雅央

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    Authorship:Coinvestigator(s) 

    神経変性疾患に共通する病態的特徴は、特定のニューロンが選択的に変性すること(空間的特異性)および中高年以降に遅発性に発症・進行すること(時間的特異性)である。本研究では、運動ニューロン疾患を研究対象とし、マウスモデルや患者由来iPSCを用い、マルチオミクスやDREADD、脳Caイメージングなどを駆使して超早期ライフステージにおけるニューロン変性分子病態とその年齢依存性変化を解明することで、神経変性における分子病態の真の起点を明らかにする。さらに、ニューロン分化と変性の関連を解析することで、選択的ニューロン死の本質的原因を究明する。

  3. Understanding of defective developmental gene regulation responsible for motor neuron degeneration

    Grant number:19H03545  2019.4 - 2022.3

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  4. Discovery of novel target and disease modifying therapy for ALS/FTLD using neuro-specific transcriptome analysis

    Grant number:17K09753  2017.4 - 2020.3

    IGUCHI YOHEI

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    Authorship:Principal investigator 

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    ALS and FTLD are progressive neurodegenerative diseases and the causes are unknown. The genetic and neuropathological studies suggest that loss of functions of TDP-43 or TBK1 are related to the neurodegeneration. We established a novel transgenic mouse, in which GFP-tagged ribosomal protein (RPL10a) and Cre are expressed under synapsin promotor. This mouse allows us to perform neuron-specific polysome (mRNA-ribosome complex) in the conditional TDP-43/TBK1 knockout mice. We validated the expression profile of GFP-RPL10a of the transgenic mouse and analyzed the neuron-specific transcriptome data of the conditional knockout mice.

  5. Elucidation of defective neural communication in motor neuron diseases

    Grant number:17H04195  2017.4 - 2020.3

    Katsuno Masahisa

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    Nuclear depletion of TDP-43 is the histopathological hallmark of amyotrophic lateral sclerosis. In this research, we showed that loss of TDP-43 inhibited exocytosis by down-regulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. In this research, we showed that DNA methyltransferase 1 is highly expressed in the motor neurons of an SBMA mouse model, and in patients with SBMA. Treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells and s the motor function of SBMA mice. We also found that the level of phosphorylated Src was markedly increased in the spinal cords and skeletal muscles of SBMA mice prior to the onset, by utilizing a phosphoprotein assay. Intraperitoneal administration of a Src kinase inhibitor improved the behavioral and histopathological phenotypes of SBMA mice.