2013 Fiscal Year Final Research Report
Identification of pathogenic domain in TDP-43 for ALS toward the antibody medicine
| Project/Area Number |
23300131
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Kyoto University (2013)
Shiga University of Medical Science (2011-2012) |
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Principal Investigator |
URUSHITANI Makoto 京都大学, 医学(系)研究科(研究院), 准教授 (60332326)
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| Co-Investigator(Kenkyū-buntansha) |
KITAHARA Ryo 立命館大学, 薬学部, 准教授 (70512284)
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| Co-Investigator(Renkei-kenkyūsha) |
ITO Hidefumi 和歌山県立医科大学, 医学部, 教授 (20250061)
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| Project Period (FY) |
2011-04-01 – 2014-03-31
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| Keywords | 筋萎縮性側索硬化症 / TDP-43 / 高圧力NMR / 抗体 / 凝集体 / 細胞モデル |
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| Research Abstract |
Using structural analyses of RNA-recognition motifs (RRM) of TDP-43, a ALS-linked protein, we identified a aberrant assembly interface in RRM1. The cysteine in the this region induced TDP-43 aggregates, cytosolic mislocalization, the incompetent RNA splicing, and cytotoxicity, which functionally and structurally mimicks TDP-43 proteinopathy. We also succeeded in cloning cDNA from murine hybridoma (3B12A), generating a monoclonal antibody recognizing the misofolded forms of TDP-43, and constructed mammalian expression plasmid for the single chain Fv (scFv). Since the commercially available transgenic mice expressing ALS-linked mutant TDP-43 (A315T) turned out to fail to replicate ALS phenotype, we newly establish the embryonic brain transfection system, using in-utero electroporation. The brain slice expressing aggregate prone mutant TDP-43 showed ALS-like TDP-43 aggregates, which could be tested to estimate the intrabody therapy.
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[Journal Article] Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 12014
Author(s)
Oono M, Okado-Matsumoto A, Shodai A,Ido A, Ohta Y, Abe K, Ayaki T, Ito H, Takahashi R, Taniguchi N, Urushitani M
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Journal Title
J Neurochem
Volume: 128
Pages: 403-418
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[Journal Article] Aberrant assembly of RNA-recognition motif 1 links to pathogenic conversion of TAR DNA-binding protein-43 (TDP-43)2013
Author(s)
Shodai A, Morimura T, Ido A, Uchida T, Ayaki T, Takahashi R, Kitazawa S, Suzuki S, Shirouzu M, Kigawa T, Muto Y, Yokoyama S, Takahashi R, Kitahara R, Ito H, Fujiwara N, Urushitani M
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Journal Title
J Biol Chem
Volume: 288, 21
Pages: 14886-14905
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[Journal Article] Motor Neuron-specific Disruption of Proteasomes, but not Autophagy, Replicates Amyotrophic Lateral Sclerosis2012
Author(s)
Tashiro Y, Urushitani M, Inoue H, Koike M, Uchiyama Y, Komatsu M, Tanaka K, Yamazaki M, Abe M, Misawa H, Sakimura K, Ito H, Takahashi R
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Journal Title
J Biol Chem
Volume: 287
Pages: 42984-4299
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[Journal Article] An autopsy case of SOD1-related ALS with TDP-43 positive inclusions2011
Author(s)
Okamoto Y, Ihara M, Urushitani M, Yamashita H, Kondo T, Tanigaki A, Oono M, Kawamata J, Ikemoto A, Kawamoto A, Takahashi R, Ito H
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Journal Title
Neurology
Volume: 77
Pages: 1995-1997
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[Journal Article] Colocalization of 14-3-3 Proteins with SOD1 in Lewy Body-Like Hyaline Inclusions in Familial Amyotrophic Lateral Sclerosis Cases and the Animal Model2011
Author(s)
Okamoto Y, Shirakashi Y, Ihara M, Urushitani M, Oono M, Kawamoto Y, Yamashita H, Shimohama S, Kato S, Hirano A, Tomimoto H, Ito H, Takahashi R
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Journal Title
PLoS ONE
Volume: 6
Pages: e20427
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