Faculty Profiles - TAKAHASHI Masahiko

写真a

TAKAHASHI Masahiko

Organization

Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Associate Professor
Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine Associate Professor

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Degree

博士(理学) ( 2004.3 筑波大学 )

Research Interests

ストレス顆粒
ウイルス感染症
タンパク凝集
細胞生存
神経変性

Research Areas

Life Science / Virology
Life Science / Pathophysiologic neuroscience
Life Science / Hematology and medical oncology

Research History (researchmap)

Niigata University Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine Associate Professor

2016.11

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Niigata University Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine Lecturer

2015.4 - 2016.10

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Niigata University Graduate School of Medical and Dental Sciences Community Disease Control Assistant Professor

2007.4 - 2015.3

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Niigata University Graduate School of Medical and Dental Sciences Assistant

2004.4 - 2007.3

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Research History

Niigata University Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine Associate Professor

2016.11
Niigata University Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine Lecturer

2015.4 - 2016.10
Niigata University Graduate School of Medical and Dental Sciences Community Disease Control Assistant Professor

2007.4 - 2015.3
Niigata University Graduate School of Medical and Dental Sciences Research Assistant

2004.4 - 2007.3

Professional Memberships

The Japanese Society for Virology

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THE JAPAN NEUROSCIENCE SOCIETY

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日本癌学会

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Papers

TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model Reviewed

Hideki Mori, Tokiharu Sato, Shintaro Tsuboguchi, Masahiko Takahashi, Yuka Nakamura, Kana Hoshina, Taisuke Kato, Masahiro Fujii, Osamu Onodera, Masaki Ueno

Neurobiology of Disease 212 106988 - 106988 2025.8

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Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

DOI： 10.1016/j.nbd.2025.106988

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UPS10 inhibits the degradation of α-synuclein, a pathogenic factor associated with Parkinson's disease, by inhibiting chaperone-mediated autophagy Reviewed

Sergei Anisimov, Masahiko Takahashi, Taichi Kakihana, Yoshinori Katsuragi, Junya Sango, Takayuki Abe, Masahiro Fujii

Journal of Biological Chemistry 110292 - 110292 2025.5

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Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

DOI： 10.1016/j.jbc.2025.110292

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Myeloid-associated differentiation marker is an essential host factor for human parechovirus PeV-A3 entry Reviewed

Kanako Watanabe, Tomoichiro Oka, Hirotaka Takagi, Sergei Anisimov, Shun-ichi Yamashita, Yoshinori Katsuragi, Masahiko Takahashi, Masaya Higuchi, Tomotake Kanki, Akihiko Saitoh, Masahiro Fujii

Nature Communications 14 ( 1 ) 2023.3

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Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Human parechovirus (PeV-A) is an RNA virus that belongs to the family Picornaviridae and it is currently classified into 19 genotypes. PeV-As usually cause mild illness in children and adults. Among the genotypes, PeV-A3 can cause severe diseases in neonates and young infants, resulting in neurological sequelae and death. In this study, we identify the human myeloid-associated differentiation marker (MYADM) as an essential host factor for the entry of six PeV-As (PeV-A1 to PeV-A6), including PeV-A3. The infection of six PeV-As (PeV-A1 to PeV-A6) to human cells is abolished by knocking out the expression of MYADM. Hamster BHK-21 cells are resistant to PeV-A infection, but the expression of human MYADM in BHK-21 confers PeV-A infection and viral production. Furthermore, VP0 capsid protein of PeV-A3 interacts with one extracellular domain of human MYADM on the cell membrane of BHK-21. The identification of MYADM as an essential entry factor for PeV-As infection is expected to advance our understanding of the pathogenesis of PeV-As.

DOI： 10.1038/s41467-023-37399-8

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Other Link： https://www.nature.com/articles/s41467-023-37399-8
USP10 inhibits aberrant cytoplasmic aggregation of TDP-43 by promoting stress granule clearance Reviewed International journal

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Osamu Onodera, Yuriko Iwakura, Hiroyuki Nawa, Masaaki Komatsu, Masahiro Fujii

Molecular and Cellular Biology 42 ( 3 ) e0039321 2022.1

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TDP-43 is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates: stress granules (SGs) first, and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that USP10 promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding dependent manner; however, impaired RNA-binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35-aggregates in the neurons of ALS patients were USP10-negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.

DOI： 10.1128/mcb.00393-21

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USP10 inhibits the dopamine-induced reactive oxygen species-dependent apoptosis of neuronal cells by stimulating the antioxidant Nrf2 activity Reviewed International journal

Junya Sango, Taichi Kakihana, Masahiko Takahashi, Yoshinori Katsuragi, Sergei Anisimov, Masaaki Komatsu, Masahiro Fujii

Journal of Biological Chemistry 298 ( 1 ) 101448 - 101448 2021.11

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Nrf2 is an antioxidant transcriptional activator in many types of cells, and its dysfunction plays key roles in a variety of human disorders, including Parkinson's disease (PD). PD is characterized by the selective loss of dopaminergic neurons in PD-affected brain regions. Dopamine treatment of neuronal cells stimulates the production of reactive oxygen species (ROS) and increases ROS-dependent neuronal apoptosis. In this study, we found that the ubiquitin-specific protease 10 (USP10) protein reduces dopamine-induced ROS production of neuronal cells and ROS-dependent apoptosis by stimulating the antioxidant activity of Nrf2. USP10 interacted with the Nrf2 activator p62, increased the phosphorylation of p62, increased the interaction of p62 with the Nrf2 inhibitor Keap1, and stimulated Nrf2 antioxidant transcriptional activity. In addition, USP10 augmented dopamine-induced Nrf2 translation. Taken together, these results indicate that USP10 is a key regulator of Nrf2 antioxidant activity in neuronal cells and suggest that USP10 activators are promising therapeutic agents for oxidative stress-related diseases, including PD.

DOI： 10.1016/j.jbc.2021.101448

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The optineurin/TIA1 pathway inhibits aberrant stress granule formation and reduces ubiquitinated TDP-43 Reviewed International journal

Taichi Kakihana, Masahiko Takahashi, Yoshinori Katsuragi, Shun-Ichi Yamashita, Junya Sango, Tomotake Kanki, Osamu Onodera, Masahiro Fujii

iScience 24 ( 7 ) 102733 - 102733 2021.7

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Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in the optineurin (OPTN) and TIA1 genes are causative factors of familial ALS with TDP-43 aggregation pathology. We found that both OPTN depletion and ALS-associated OPTN mutations upregulated the TIA1 level in cells recovered from heat shock, and this upregulated TIA1 increased the amount of ubiquitinated TDP-43. Ubiquitinated TDP-43 induced by OPTN depletion was localized in SGs. Our study suggests that ALS-associated loss-of-function mutants of OPTN increase the amount of ubiquitinated TDP-43 in neurons by increasing the expression of TIA1, thereby promoting the aggregation of ubiquitinated TDP-43.

DOI： 10.1016/j.isci.2021.102733

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Antitumor Effect of Sugar-Modified Cytosine Nucleosides on Growth of Adult T-Cell Leukemia Cells in Mice Reviewed International journal

Naoyoshi Maeda, Akira Matsuda, Satoko Otsuguro, Masahiko Takahashi, Masahiro Fujii, Katsumi Maenaka

Vaccines 8 ( 4 ) 658 - 658 2020.11

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Adult T-cell leukemia (ATL) is a CD4+ T-cell neoplasm caused by human T-cell leukemia virus type I. As the prognosis for patients with ATL remains extremely poor due to resistance to conventional chemotherapy regimens, introduction of novel therapeutic agents is needed. Previous studies have reported that nucleosides 2′-deoxy-2′-methylidenecytidine (DMDC) and its derivative 2′-deoxy-2′-methylidene-5-fluorocytidine (FDMDC) exhibit antitumor activities in T-cell acute lymphoblastic leukemia (T-ALL) and solid tumor cell lines. Another nucleoside, 1-(2-azido-2-deoxy-β-D-arabinofuranosyl)cytosine (cytarazid), is considered a therapeutic drug with antitumor activity in human solid tumors. In this study, we investigated the effects of these nucleosides on cell growth in vitro and in vivo using relevant leukemia cell lines and NOD/Shi-scid, IL-2Rgnull (NOG) mice, respectively. The nucleosides demonstrated significant cytotoxic effects in ATL and T-ALL cell lines. Intraperitoneal administration of FDMDC and DMDC into tumor-bearing NOG mice resulted in significant suppression of tumor growth without lethal side effects. Our findings support a therapeutic application of these nucleosides against tumor progression by targeting DNA polymerase-dependent DNA synthesis in patients with ATL.

DOI： 10.3390/vaccines8040658

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USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells Reviewed International journal

Svetlana Piatnitskaia, Masahiko Takahashi, Hiroki Kitaura, Yoshinori Katsuragi, Taichi Kakihana, Lu Zhang, Akiyoshi Kakita, Yuriko Iwakura, Hiroyuki Nawa, Takeshi Miura, Takeshi Ikeuchi, Toshifumi Hara, Masahiro Fujii

Scientific Reports 9 ( 1 ) 10591 - 10591 2019.12

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Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer's disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.

DOI： 10.1038/s41598-019-47033-7

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Other Link： http://www.nature.com/articles/s41598-019-47033-7
G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10 Reviewed International journal

Sergei Anisimov, Masahiko Takahashi, Taichi Kakihana, Yoshinori Katsuragi, Hiroki Kitaura, Lu Zhang, Akiyoshi Kakita, Masahiro Fujii

Scientific Reports 9 ( 1 ) 12896 - 12896 2019.12

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The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

DOI： 10.1038/s41598-019-46237-1

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Other Link： http://www.nature.com/articles/s41598-019-46237-1
USP10 Inhibits Ubiquitinated Protein Oligomer Toxicity by Inducing Protein Aggregates and Aggresomes

Masahiko Takahashi, Svetlana Piatnitskaia, Sergei Anisimov

NIIGATA MEDICAL JOURNAL 133 ( 3 ) 91 - 96 2019.3

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USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis Reviewed International journal

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Masaaki Nameta, Lu Zhang, Yuriko Iwakura, Hiroyuki Nawa, Masaya Higuchi, Masaaki Komatsu, Masahiro Fujii

iScience 9 433 - 450 2018.11

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Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing α-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with α-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits α-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases.

DOI： 10.1016/j.isci.2018.11.006

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MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia Reviewed

Takashi Kozakai, Masahiko Takahashi, Masaya Higuchi, Toshifumi Hara, Kousuke Saito, Yuetsu Tanaka, Masayoshi Masuko, Jun Takizawa, Hirohito Sone, Masahiro Fujii

International Journal of Hematology 107 ( 3 ) 337 - 344 2018.3

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DOI： 10.1007/s12185-017-2359-1

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USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells Reviewed

Masaya Higuchi, Hiroki Kawamura, Hideaki Matsuki, Toshifumi Hara, Masahiko Takahashi, Suguru Saito, Kousuke Saito, Shuying Jiang, Makoto Naito, Hiroshi Kiyonari, Masahiro Fujii

Stem Cell Reports 7 ( 6 ) 1116 - 1129 2016.12

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DOI： 10.1016/j.stemcr.2016.11.003

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Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB Reviewed

Yosuke Motai, Masahiko Takahashi, Takayuki Takachi, Masaya Higuchi, Toshifumi Hara, Mariko Mizuguchi, Yutaka Aoyagi, Shuji Terai, Yuetsu Tanaka, Masahiro Fujii

Virus Genes 52 ( 1 ) 4 - 13 2016.2

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DOI： 10.1007/s11262-015-1277-7

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Other Link： http://link.springer.com/article/10.1007/s11262-015-1277-7/fulltext.html
RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells Reviewed

Suguru Saito, Toshihiko Kawamura, Masaya Higuchi, Takahiro Kobayashi, Manami Yoshita-Takahashi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Yasuhiro Kanda, Hiroki Kawamura, Shuying Jiang, Makoto Naito, Takumi Yoshizaki, Masahiko Takahashi, Masahiro Fujii

European Journal of Immunology 45 ( 5 ) 1512 - 1523 2015.5

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DOI： 10.1002/eji.201444977

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Human T ‐cell leukemia virus type 1 T ax oncoprotein represses the expression of the BCL 11 B tumor suppressor in T ‐cells Reviewed

Takayuki Takachi, Masahiko Takahashi, Manami Takahashi‐Yoshita, Masaya Higuchi, Miki Obata, Yukio Mishima, Shujiro Okuda, Yuetsu Tanaka, Masao Matsuoka, Akihiko Saitoh, Patrick L. Green, Masahiro Fujii

Cancer Science 106 ( 4 ) 461 - 465 2015.4

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DOI： 10.1111/cas.12618

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.12618
Downregulation of proapoptotic Bim augments IL ‐2‐independent T‐cell transformation by human T‐cell leukemia virus type‐1 Tax Reviewed

Masaya Higuchi, Masahiko Takahashi, Yuetsu Tanaka, Masahiro Fujii

Cancer Medicine 3 ( 6 ) 1605 - 1614 2014.12

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DOI： 10.1002/cam4.329

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cam4.329
HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10 Reviewed

Masahiko Takahashi, Masaya Higuchi, Grace Naswa Makokha, Hideaki Matsuki, Manami Yoshita, Yuetsu Tanaka, Masahiro Fujii

Blood 122 ( 5 ) 715 - 725 2013.8

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DOI： 10.1182/blood-2013-03-493718

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Human T-cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI-1 Reviewed

Grace Naswa Makokha, Masahiko Takahashi, Masaya Higuchi, Suguru Saito, Yuetsu Tanaka, Masahiro Fujii

Cancer Science 104 ( 3 ) 313 - 320 2013.3

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DOI： 10.1111/cas.12087

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Stress Granules Inhibit Apoptosis by Reducing Reactive Oxygen Species Production Reviewed

M. Takahashi, M. Higuchi, H. Matsuki, M. Yoshita, T. Ohsawa, M. Oie, M. Fujii

Molecular and Cellular Biology 33 ( 4 ) 815 - 829 2013.2

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Authorship：Lead author Publishing type：Research paper (scientific journal) Publisher：American Society for Microbiology

DOI： 10.1128/mcb.00763-12

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Both G3BP1 and G3BP2 contribute to stress granule formation Reviewed

Hideaki Matsuki, Masahiko Takahashi, Masaya Higuchi, Grace N Makokha, Masayasu Oie, Masahiro Fujii

Genes to Cells 18 ( 2 ) 135 - 146 2013.2

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DOI： 10.1111/gtc.12023

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Human T cell leukemia virus type 2 (HTLV-2) Tax2 has a dominant activity over HTLV-1 Tax1 to immortalize human CD4+ T cells Reviewed

Michitaka Imai, Masaya Higuchi, Hiroki Kawamura, Manami Yoshita, Masahiko Takahashi, Masayasu Oie, Hideaki Matsuki, Yuetsu Tanaka, Yutaka Aoyagi, Masahiro Fujii

Virus Genes 46 ( 1 ) 39 - 46 2013.2

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DOI： 10.1007/s11262-012-0831-9

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Other Link： http://link.springer.com/article/10.1007/s11262-012-0831-9/fulltext.html
Mechanisms of pathogenesis induced by bovine leukemia virus as a model for human T-cell leukemia virus Reviewed

Yoko Aida, Hironobu Murakami, Masahiko Takahashi, Shin-Nosuke Takeshima

Frontiers in Microbiology 4 2013

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DOI： 10.3389/fmicb.2013.00328

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Activation of mTOR by human T-cell leukemia virus type 1 Tax is important for the transformation of mouse T cells to interleukin-2-independent growth Reviewed

Manami Yoshita, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Masahiro Fujii

Cancer Science 103 ( 2 ) 369 - 374 2012.2

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DOI： 10.1111/j.1349-7006.2011.02123.x

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The PDZ domain binding motif (PBM) of human T-cell leukemia virus type 1 Tax can be substituted by heterologous PBMs from viral oncoproteins during T-cell transformation Reviewed

Tomoya Aoyagi, Masahiko Takahashi, Masaya Higuchi, Masayasu Oie, Yuetsu Tanaka, Tohru Kiyono, Yutaka Aoyagi, Masahiro Fujii

Virus Genes 40 ( 2 ) 193 - 199 2010.4

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DOI： 10.1007/s11262-009-0447-x

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Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-κB Reviewed

Tiejun Zhao, Jun-ichirou Yasunaga, Yorifumi Satou, Mitsuyoshi Nakao, Masahiko Takahashi, Masahiro Fujii, Masao Matsuoka

Blood 113 ( 12 ) 2755 - 2764 2009.3

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DOI： 10.1182/blood-2008-06-161729

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Identification of a novel motif responsible for the distinctive transforming activity of human T-cell leukemia virus (HTLV) type 1 Tax1 protein from HTLV-2 Tax2 Reviewed

Toshiyuki Shoji, Masaya Higuchi, Rie Kondo, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Yutaka Aoyagi, Masahiro Fujii

Retrovirology 6 ( 1 ) 83 - 83 2009

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DOI： 10.1186/1742-4690-6-83

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Human T-cell leukemia virus type 1 Tax induces an aberrant clustering of the tumor suppressor Scribble through the PDZ domain-binding motif dependent and independent interaction Reviewed

Masaaki Okajima, Masahiko Takahashi, Masaya Higuchi, Toshiaki Ohsawa, Sakiko Yoshida, Yutaka Yoshida, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Masahiro Fujii

Virus Genes 37 ( 2 ) 231 - 240 2008.10

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DOI： 10.1007/s11262-008-0259-4

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Knockdown of synapse-associated protein Dlg1 reduces syncytium formation induced by human T-cell leukemia virus type 1 Reviewed

Sakiko Yoshida, Masaya Higuchi, Toshiyuki Shoji, Manami Yoshita, Kojiro Ishioka, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Makoto Uchiyama, Masahiro Fujii

Virus Genes 37 ( 1 ) 9 - 15 2008.8

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DOI： 10.1007/s11262-008-0234-0

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Other Link： http://link.springer.com/article/10.1007/s11262-008-0234-0/fulltext.html
Rearranged NF-κB2 gene in an adult T-cell leukemia cell line Reviewed

Masato Isogawa, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Naoki Mori, Yuetsu Tanaka, Yutaka Aoyagi, Masahiro Fujii

Cancer Science 99 ( 4 ) 792 - 798 2008.4

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DOI： 10.1111/j.1349-7006.2008.00750.x

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Cooperation of NF-κB2/p100 Activation and the PDZ Domain Binding Motif Signal in Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax1 but Not HTLV-2 Tax2 Is Crucial for Interleukin-2-Independent Growth Transformation of a T-Cell Line Reviewed

Masaya Higuchi, Chikako Tsubata, Rie Kondo, Sakiko Yoshida, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Renaud Mahieux, Masao Matsuoka, Masahiro Fujii

Journal of Virology 81 ( 21 ) 11900 - 11907 2007.11

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DOI： 10.1128/jvi.00532-07

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A novel KRAB-Zinc finger protein interacts with latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus and activates transcription via terminal repeat sequences Reviewed

Akiko Watanabe, Masaya Higuchi, Masaya Fukushi, Toshiaki Ohsawa, Masahiko Takahashi, Masayasu Oie, Masahiro Fujii

Virus Genes 34 ( 2 ) 127 - 136 2007.3

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DOI： 10.1007/s11262-006-0048-x

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Other Link： http://link.springer.com/article/10.1007/s11262-006-0048-x/fulltext.html
Human T-cell leukemia virus type 2 Tax protein induces interleukin 2-independent growth in a T-cell line. Reviewed

Rie Kondo, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Masahiro Fujii

Retrovirology 3 ( 1 ) 88 - 88 2006

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DOI： 10.1186/1742-4690-3-88

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Inactivation of tumor suppressor Dlg1 augments transformation of a T-cell line induced by human T-cell leukemia virus type 1 Tax protein. Reviewed

Kojiro Ishioka, Masaya Higuchi, Masahiko Takahashi, Sakiko Yoshida, Masayasu Oie, Yuetsu Tanaka, Sugata Takahashi, Li Xie, Patrick L Green, Masahiro Fujii

Retrovirology 3 ( 1 ) 71 - 71 2006

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DOI： 10.1186/1742-4690-3-71

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Aberrant Activation of the Interleukin-2 Autocrine Loop through the Nuclear Factor of Activated T Cells by Nonleukemogenic Human T-Cell Leukemia Virus Type 2 but Not by Leukemogenic Type 1 Virus Reviewed International journal

Akiko Niinuma, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Nobuyuki Tanaka, Kazuo Sugamura, Li Xie, Patrick L. Green, Masahiro Fujii

Journal of Virology 79 ( 18 ) 11925 - 11934 2005.9

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DOI： 10.1128/jvi.79.18.11925-11934.2005

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PubMed

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Involvement of bovine leukemia virus in induction and inhibition of apoptosis Reviewed

Masahiko Takahashi, Shigeru Tajima, Kosuke Okada, William C. Davis, Yoko Aida

Microbes and Infection 7 ( 1 ) 19 - 28 2005.1

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DOI： 10.1016/j.micinf.2004.09.014

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PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein is essential for the interleukin 2 independent growth induction of a T-cell line. Reviewed

Chikako Tsubata, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Masahiro Fujii

Retrovirology 2 ( 1 ) 46 - 46 2005

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DOI： 10.1186/1742-4690-2-46

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Elevated expression of CD30 in adult T-cell leukemia cell lines: possible role in constitutive NF-kappaB activation. Reviewed International journal

Masaya Higuchi, Takehiro Matsuda, Naoki Mori, Yasuaki Yamada, Ryouichi Horie, Toshiki Watanabe, Masahiko Takahashi, Masayasu Oie, Masahiro Fujii

Retrovirology 2 ( 1 ) 29 - 29 2005

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DOI： 10.1186/1742-4690-2-29

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Ex vivo survival of peripheral blood mononuclear cells in sheep induced by bovine leukemia virus (BLV) mainly occurs in CD5– B cells that express BLV Reviewed International journal

Masahiko Takahashi, Shigeru Tajima, Shin-Nosuke Takeshima, Satoru Konnai, Shan Ai Yin, Kosuke Okada, William C. Davis, Yoko Aida

Microbes and Infection 6 ( 6 ) 584 - 595 2004.5

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DOI： 10.1016/j.micinf.2004.02.014

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A Mutant Form of the Tax Protein of Bovine Leukemia Virus (BLV), with Enhanced Transactivation Activity, Increases Expression and Propagation of BLV In Vitro but Not In Vivo Reviewed

Shigeru Tajima, Masahiko Takahashi, Shin-nosuke Takeshima, Satoru Konnai, Shan Ai Yin, Shinobu Watarai, Yoshimasa Tanaka, Misao Onuma, Kosuke Okada, Yoko Aida

Journal of Virology 77 ( 3 ) 1894 - 1903 2003.2

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DOI： 10.1128/jvi.77.3.1894-1903.2003

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CiNii Article

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MISC

成人T細胞白血病ウイルス癌蛋白TaxとHBZはBCL11B遺伝子発現を抑制する(Human T-cell leukemia virus type 1 oncoproteins Tax and HBZ represses BCL11B gene expression)

高地貴行, 由田真奈美, 高橋雅彦, 樋口雅也, 大家正泰, 小幡美貴, 三嶋行雄, 木南凌, 松岡雅雄, 藤井雅寛

日本癌学会総会記事 72回 240 - 240 2013.10

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Language：English Publisher：日本癌学会

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Aberrant activation of the interleukin 2 autocrine loop through Nfat by non-leukemogenic human T-cell leukemia virus type 2 but not leukemogenic type 1 virus

M Fujii, M Takahashi, M Higuchi

AIDS RESEARCH AND HUMAN RETROVIRUSES 21 ( 5 ) 451 - 451 2005.5

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Oncogenesis by a Human Retrovirus (Genome Information and Infection (Application for Diagnosis, Treatment, and Prevention))

FUJII Masahiro, HIRATA Akira, NIINUMA Akiko, TSUBATA Chikako, ISHIOKA Koujirou, Jo Rie, TAKAHASHI Masahiko, OIE Masayasu, HIGUCHI Masaya

Niigata medical journal 118 ( 11 ) 601 - 606 2004.11

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Language：Japanese Publisher：Niigata University

Human T-cell leukemia virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia (ATL). Around 5% HTLV-1-infected individuals develop ATL averagely 50-60 years after the infection. Thus, in addition to HTLV-1, multiple host factors are involved in the development of ATL. Unlike to HTLV-1, an allied virus HTLV-2 is not associated with ATL or similar leukemia. HTLV-1 and HTLV-2 immortalizes human T-cells in vitro, and their efficiencies are equivalent. These results suggest that HTLV-1 has additional activities to host T-cells resulting in ATL development. We will discuss the roles of HTLV-1 tax1 and HTLV-2 tax2 genes in the distinct pathogenic activities between two viruses.

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Other Link： http://hdl.handle.net/10191/2541
モノクローナル抗体による牛白血病ウイルス表面抗原gp51の検出

若本裕晶, 森田裕, 高橋雅彦, 間陽子

日本獣医学会学術集会講演要旨集 135回 123 - 123 2003.3

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Language：Japanese Publisher：(公社)日本獣医学会

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In vitro and in vivo analyses of infectious molecular clone of BLV encoding tax with elevated transactivation activity

S Tajima, M Takahashi, K Okada, Y Aida

AIDS RESEARCH AND HUMAN RETROVIRUSES 17 S48 - S48 2001

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Presentations

USP10 inhibits aberrant cytoplasmic aggregation of TDP-43 by promoting stress granule clearance

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Osamu Onodera, Masahiro Fujii

NEURO2022（沖縄） 2022.7

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G3BP1 and USP10 prevent aberrant cytoplasmic TDP-43 aggregation through interacting with TDP-43

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Akihide Koyama, Osamu Onodera, Yuriko Iwakura, Hiroyuki Nawa, Masaaki Komatsu, Masahiro Fujii

第43回日本神経科学大会（大阪） 2020.8

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USP10 is a critical factor in α-synuclein aggregation, aggresome and Lewy body formations but not GCI

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Masaaki Nameta, Yuriko Iwakura, Hiroyuki Nawa, Masaya Higuchi, Masaaki Komatsu, Masahiro Fujii

24th World Congress of Neurology 2019 (アラブ首長国連邦・ドバイ) 2019.10

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USP10 is a critical factor for aggresome formation to induce α-synuclein aggregation and Lewy body but not GCI

Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Masaaki Nameta, Yuriko Iwakura, Hiroyuki Nawa, Masaya Higuchi, Masaaki Komatsu, Masahiro Fujii

NEURO2019（新潟） 2019.7

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HTLV-1の Tax蛋白はUSP10を介してROS産生とROS依存性アポトーシスを誘導する

髙橋雅彦, 樋口雅也, 藤井雅寛

第61回日本ウイルス学会学術集会（神戸） 2013.11

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HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T-cells by interacting with USP10

Masahiko Takahashi, Masaya Higuchi, Masahiro Fujii

第72回日本癌学会学術総会（横浜） 2013.10

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Stress granules inhibit apoptosis by reducing ROS production, but this phenomenon is nullified by HTLV-1 Tax

Masahiko Takahashi, Masaya Higuchi, Masahiro Fujii

16th International Conference on Human Retrovirology HTLV and Related Viruses（カナダ・モントリオール） 2013.6

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ストレス顆粒はROS産生を抑制することによりアポトーシスを阻害するが、これをHTLV-1の Tax1は解除する

髙橋雅彦, 樋口雅也, 藤井雅寛

第71回日本癌学会学術総会（札幌） 2012.9

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HTLV-1 Taxは脱ユビキチン化酵素USP10によるストレス誘導性アポトーシスの抑制を解除する

髙橋雅彦, 樋口雅也, 藤井雅寛

第69回日本癌学会学術総会（札幌） 2010.9

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HTLV-1 によるストレス応答の抑制

髙橋雅彦, 樋口雅也, 松木秀明, 藤井雅寛

第57回日本ウイルス学会学術集会（東京） 2009.10

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変異体Taxを有する牛白血病ウイルス（BLV）によるアポトーシス制御

髙橋雅彦, 田島茂, 岡田幸助, 間陽子

第51回日本ウイルス学会学術集会（京都） 2003.10

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Regulation of Apoptosis induced by Bovine Leukemia Virus Encoding Tax with Elevated Transactivation Activity

Takahashi M, Tajima S, Okada K, Aida Y

11th International Conference on Human Retrovirology, HTLV and Related Viruses（USA・サンフランシスコ） 2003.6

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BLV産生細胞におけるアポトーシス制御

髙橋雅彦, 田島茂, 岡田幸助, 間陽子

第135回日本獣医学会学術集会（東京） 2003.3

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BLV感染羊由来PBMCのex vivo 培養におけるアポトーシス関連因子の発現

髙橋雅彦, 田島茂, 高木道浩, 小沼操, 間陽子

第50回日本ウイルス学会学術集会（札幌） 2002.10

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BLV感染羊由来PBMCのex vivo培養におけるアポトーシス関連因子の発現

髙橋雅彦, 田島茂, 岡田幸助, 尹善愛, 高木道浩, 小沼操, 間陽子

第133回日本獣医学会学術集会（日本獣医畜産大学） 2002.3

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ex vivo 培養におけるBLV感染羊由来CD5陽性および陰性Ｂ細胞のアポトーシス抑制効果の解析

髙橋雅彦, 田島茂, 今内覚, 小沼操, 間陽子

第49回日本ウイルス学会学術集会（大阪） 2001.11

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BLV感染羊におけるCD5陰性Ｂ細胞特異的なアポトーシスの抑制

髙橋雅彦, 田島茂, 岡田幸助, 小沼操, 間陽子

第131回日本獣医学会学術集会（東京農工大学） 2001.4

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高活性型tax遺伝子を有するウシ白血病ウイルス（BLV）感染性分子クローンの解析

髙橋雅彦, 田島茂, 間陽子

第129回日本獣医学会学術集会（つくば国際会議場） 2000.4

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Research Projects

RNA結合活性が低下したTDP-43の凝集体形成機構の解明

Grant number：25K10622

2025.4 - 2028.3

System name：科学研究費助成事業

Research category：基盤研究(C)

Awarding organization：日本学術振興会

高橋雅彦

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

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ウイルス感染を引き金としたアルツハイマー病タウ蓄積の分子機構

2024.10 - 2026.3

System name：第57回「医学研究助成」

Awarding organization：公益財団法人大樹生命厚生財団

髙橋雅彦

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多発性骨髄腫患者にて分子標的薬ダラツムマブによる輸血検査偽陽性の新規回避法の確立

Grant number：21K07201

2021.4 - 2025.3

System name：科学研究費助成事業

Research category：基盤研究(C)

Awarding organization：日本学術振興会

川村宏樹, 高橋雅彦

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

【目的】多発性骨髄腫に発現するCD38の分子標的治療薬であるダラツムマブ（DARA）は、赤血球にもCD38が発現していためにDARA投与患者の輸血検査で偽陽性となり問題となっている。そこで本研究は、CD38陽性骨髄腫細胞株を用いてDARAの吸着法の確立を目指す。令和5年度は全ての検討をカラム凝集法に変更して骨髄腫細胞株の洗浄方法と吸着法の見直しを血漿にDARAを加えた模擬検体を用いておこない、その後に不規則抗体陽性FFPを加えたDARA模擬検体で検出に与える影響を検討した。
【成果】初めにカラム凝集法で抗IgGカセットをDARA陽性模擬検体で使用した結果、クームスカセットより安定してDARA濃度0.1μg/mL～100μg/mLで1+～2+の凝集強度が認められたので、研究では抗IgGカセットを使用することにした。
次に昨年までは吸着するための加温時間が3～6時間かかったので、吸着法の再検討をおこなった。その結果、CD38陽性骨髄腫細胞株（α細胞またはβ細胞）の洗浄法を変え、0.1μg/mLと10μg/mLの模擬検体量に対して同量の吸着用細胞の沈査容量を見直したところ、1時間の加温時間で1+がW+以下に凝集強度が低下した。
次にPBSで1+に調整した抗Eまたは抗Diaの陽性FFPに10μg/mLになるようにDARAを加えて作成した検体に吸着法を実施して、不規則抗体検査に与える影響を検討した。その結果、吸着法実施後にPBS-DARA(+)の対象と抗E-DARA(+)または抗D-DARA(+)を比べたところ、抗E-DARA(+)または抗D-DARA(+)に凝集強度の増加が確認され不規則抗体陽性と判定できた。
現在、予備実験の結果ではあるが低イオン強度液を使用してDARAの吸着効率および時間短縮が可能な結果を得たため、条件検討とCD38陽性骨髄腫細胞株の保存法の検討を進めている。

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USP10 in LPS-stimulated macrophages acts on Regnase-1 to suppress inflammatory cytokines.

Grant number：17K08795

2017.4 - 2022.3

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

KAWAMURA Hiroki

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Grant amount：\4810000 （ Direct Cost: \3700000 、 Indirect Cost：\1110000 ）

This study examined the effect of USP10 on inflammatory cytokine production in macrophages. Stimulation of USP10-KD J774 cells with the TLR4 ligand LPS resulted in decreased proliferative capacity compared to Ren J774 cells, while TNFα, IL-6 and MIP-2 (CXCL2) were significantly increased, and additional stimulation with Nigericn significantly increased IL-1β.These increases in proinflammatory cytokine production capacity were different with TLR2 ligand stimulation and were specific to TLR4 stimulation.This inflammatory response differs from previously reported pathways in which USP10 suppresses NFκ-B activity, suggesting that USP10 affects inflammatory cytokine production through its involvement in the regulation of mRNA levels by Regnase-1. This is a new observation of the inflammatory response, but the pathway of involvement of USP10 in Regnase-1 needs to be clarified. We will further continue this study to contribute to the treatment of inflammatory bowel disease in the future.

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Elucidation of a novel molecular mechanism that suppresses sensitivity to proteasome inhibitors

Grant number：17K09918

2017.4 - 2020.3

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

Takahashi Masahiko

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

Adult T-cell leukemia (ATL) is a CD4-positive T-cell leukemia caused by infection of human T-cell leukemia virus type 1 (HTLV-1). We identified ubiquitin-specific protease 10 (USP10) as a cellular factor that binds to the HTLV-1 Tax protein. In ATL cells, reduced USP10 expression promoted apoptosis induced by proteasome inhibitor, indicating that USP10 enhances ATL cell viability. Analysis of this molecular mechanism revealed that USP10 aggregates cytotoxic ubiquitinated proteins to form aggresome and inactivates the toxicity.

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ストレス顆粒とオートファジーによるTDP-43蛋白の分解機構

2016 - 2018

System name：医学系研究奨励（基礎）

Awarding organization：武田科学振興財団

高橋雅彦

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Elucidation of pathogenic mechanism of adult T-cell leukemia induced by abnormal ROS regulation

Grant number：26461417

2014.4 - 2017.3

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Scientific Research (C)

Awarding organization：Japan Society for the Promotion of Science

Takahashi Masahiko

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Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

Adult T-cell leukemia (ATL) is an aggressive hematologic malignancy of poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1), and it is imperative to develop therapeutic drugs for chemotherapy against ATL. As arsenite or proteasome inhibitor bortezomib induce cell death in HTLV-1-infected T-cells, antitumor effect on ATL can be expected by using these drugs. In this study, we identified that ubiquitin-specific protease 10 (USP10) confers drug resistance phenotype to HTLV-1-infected T-cells. Based on this result, we are currently attempting to identify cellular defense mechanism against drug treatment that USP10 is involved.

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活性酸素制御分子USP10の成人T細胞白血病発症における役割

2013

System name：新潟大学プロジェクト推進経費

Awarding organization：新潟大学

髙橋雅彦

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The pathogenic mechanism of HTLV-1 leukemogenesis via novel binding protein of Tax1

Grant number：23790498

2011 - 2012

System name：Grants-in-Aid for Scientific Research

Research category：Grant-in-Aid for Young Scientists (B)

Awarding organization：Japan Society for the Promotion of Science

TAKAHASHI Masahiko

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Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

We examined functional roles of USP10 and its binding partner G3BP1. We found that G3BP1 elevates the steady-state ROS level by inhibiting the antioxidant activity of USP10. However, following exposure to arsenic, G3BP1 and USP10 induce the formation of stress granules, which uncovers the antioxidant activity of USP10. We also found that the antioxidant activity of USP10 requires the protein kinase activity of ATM.

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新規脱ユビキチン化酵素によるHTLV-1発癌性の制御

2008

System name：新潟大学プロジェクト推進経費

Awarding organization：新潟大学

髙橋雅彦

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新規脱ユビキチン化酵素によるNF-κB活性の抑制と発がんウイルス蛋白によるその解除

2007

System name：新潟大学プロジェクト推進経費

Awarding organization：新潟大学

髙橋雅彦

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HTLV-1の高発癌性を決める分子機構

2006

System name：新潟大学塚田医学奨学金

Awarding organization：新潟大学

髙橋雅彦

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発がんウイルスHTLV-1の組織特異的潜伏感染機構

2006

System name：新潟大学プロジェクト推進経費

Awarding organization：新潟大学

髙橋雅彦

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HTLV-1遺伝子発現のエピジェネティックな抑制機構

Grant number：17790303

2005 - 2006

System name：科学研究費助成事業

Research category：若手研究(B)

Awarding organization：日本学術振興会

高橋雅彦

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Grant amount：\3500000 （ Direct Cost: \3500000 ）

ヒトT細胞白血病ウイルス1型(HTLV-1)は成人T細胞白血病(ATL)の原因ウイルスである。HTLV-1はCD4陽性T細胞特異的に潜伏感染し、平均50年の潜伏期間を経てATLを発症する。本研究ではヌクレオソーム構造変換に関わるクロマチンリモデリング因子がHTLV-1潜伏過程に関与するのか否かを検討するため、以下の解析を行った。
1.まずクロマチンリモデリング因子hBrm存在下におけるHTLV-1プロモーター活性を検討した。HTLV-1プロモーターの下流側にルシフェラーゼ遺伝子を連結したレポーターベクターを用いてルシフェラーゼ活性を測定したところ、HTLV-1プロモーター活性はhBrm存在下において抑制されることが明らかとなった。
2.次にウイルス自身がコードする転写活性化因子Taxが上記の現象に関与するのか否か解析した。興味深いことに、hBrmによって誘導されるHTLV-1プロモーター活性の抑制はTaxによって解除されると同時に、転写亢進を誘導することが明らかとなった。さらにその分子メカニズムを検討するため、Tax存在下および非存在下においてhBrmがHTLV-1プロモーターに結合するか否かをクロマチン免疫沈降法により解析した。すると、Tax非存在下ではhBrmがHTLV-1プロモーターに結合したが、Tax存在下ではプロモーター結合活性が消失していた。
3.hBrmの発現は一部ヒトがん細胞株において欠損する傾向がある。そこで、複数のATL由来細胞株におけるhBrmの発現動態を解析したところ、調べたすべての細胞株においてhBrmが安定に発現していた。興味深いことにHTLV-1のターゲットであるCD4陽性T細胞においてhBrmが強く発現していることが報告されており、上記の結果はウイルス潜伏過程においてhBrmが有利に作用する可能性を示唆する。

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白血病ウイルス感染細胞の悪性化機構

2004

System name：新潟大学プロジェクト推進経費

Awarding organization：新潟大学

髙橋雅彦

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Authorship：Principal investigator

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Teaching Experience (researchmap)

分子ウイルス学（大学院修士課程）

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ウイルス学講義（卒前教育）

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ウイルス学実習（卒前教育）

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医学研究実習（卒前教育）

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ヒト免疫不全ウイルス（大学院修士課程）

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Teaching Experience

生体防御と感染(ウイルス学)

2024
Institution name：新潟大学