Investigation of pathomechanism and novel therapeutic strategy for ALS on the basis of optineurin dysfunction
| Project/Area Number |
24300132
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Wakayama Medical University |
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Principal Investigator |
Ito Hidefumi 和歌山県立医科大学, 医学部, 教授 (20250061)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAMOTO YASUHIRO 京都大学, 医学研究科, 非常勤講師 (40335253)
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| Co-Investigator(Renkei-kenkyūsha) |
KAWAKAMI HIDESHI 広島大学, 原爆放射線医科学研究所, 教授 (70253060)
RYOSUKE TAKAHASHI 京都大学, 医学研究科, 教授 (90216771)
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| Project Period (FY) |
2012-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2012: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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| Keywords | オプチニューリン / 筋萎縮性側索硬化症 / NF-κB / ゴルジ装置断片化 / 炎症性サイトカイン / NF-кB |
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| Outline of Final Research Achievements |
We knocked down OPTN in neuronal cells and examined the resulting NF-κB activity and phenotype. First, we confirmed the loss of the endogenous OPTN expression after siRNA treatment and found that NF-κB activity was increased in OPTN-knockdown cells. Next, we found that OPTN knockdown caused neuronal cell death. Then, overexpression of OPTN WT or OPTN E50K with intact NF-jB-suppressive activity, but not overexpression of ALS-related OPTN mutants, suppressed the neuronal death induced by OPTN knockdown. This neuronal cell death was inhibited by withaferin A, which selectively inhibits NF-κB activation. Lastly, involvement of the mitochondrial proapoptotic pathway was suggested for neuronal death induced by OPTN knockdown. Taken together, these results indicate that inappropriate NF-jB activation is the pathogenic mechanism underlying OPTN mutation-related ALS.
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Report
(5 results)
Research Products
(66 results)
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[Journal Article] CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS2016
Author(s)
Uchida T, Tamaki Y, Ayaki T, Shodai A, Kaji S, Morimura T, Banno Y, Nishitsuji K, Sakashita N, Maki T, Yamashita H, Ito H, Takahashi R, Urushitani M.
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Journal Title
Sci Rep
Volume: 6
Pages: 19118-19118
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant.2014
Author(s)
Ayaki T, Ito H, Fukushima H, Inoue T, Kondo T, Ikemoto A, Asano T, Shodai A, Fujita T, Fukui S, Morino H, Nakano S, Kusaka H, Yamashita H, Ihara M, Matsumoto R, Kawamata J, Urushitani M, Kawakami H, Takahashi R.
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Journal Title
Acta Neuropathol Commun.
Volume: 2
Pages: 172-172
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation.2014
Author(s)
Kamada M, Izumi Y, Ayaki T, Nakamura M, Kagawa S, Kudo E, Sako W, Maruyama H, Nishida Y, Kawakami H, Ito H, Kaji R
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Journal Title
Neuropathology.
Volume: 34(1)
Pages: 64-70
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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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（3）
Pages: 403-18
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] An autopsy case of sporadic amyotrophic lateral sclerosis associated with the I113T SOD1 mutation.2014
Author(s)
Nakamura S, Wate R, Kaneko S, Ito H, Oki M, Tsuge A, Nagashima M, Asayama S, Fujita K, Nakamura M, Maruyama H, Kawakami H, Kusaka H
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Journal Title
Neuropathology.
Volume: 34(1)
Pages: 58-63
DOI
Related Report
Peer Reviewed
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[Journal Article] Aberrant Assembly of RNA Recognition Motif 1 Links to Pathogenic Conversion of TAR DNA-binding Protein of 43 kDa (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
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] ATP13A2 Deficiency Induces a Decrease in Cathepsin D Activity, Fingerprint-like Inclusion, and Selective Degeneration of Dopaminergic Neurons2013
Author(s)
Matsui H, Sato F, Sato S, Koike M, Taruno Y, Saiki S, Funayama M, Ito H, Taniguchi Y, Uemura N, Toyoda A, Sakaki Y, Takeda S, Uchiyama Y, Hattori N, Takahashi R.
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Journal Title
FEBS Letters
Volume: 587(9)
Pages: 1316-1325
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates.2013
Author(s)
Matsui H, Gavinio R, Asano T, Uemura N, Ito H, Taniguchi Y, Kobayashi Y, Maki T, Shen J, Takeda S, Uemura K, Yamakado H, Takahashi R.
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Journal Title
Hum Mol Genet.
Volume: 22(12)
Pages: 1-1
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] 抗U3RNP抗体陽性筋炎の1例2014
Author(s)
村田顕也, 中西一郎, 池田高治, 三森経世, 伊東秀文
Organizer
第55回日本神経病理学会総会学術研究会
Place of Presentation
学術総合センター 一橋講堂
Year and Date
2014-06-06
Related Report
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[Presentation] アルツハイマー型認知症における自己記入式質問票の有用性の検討2014
Author(s)
檜皮谷泰寛, 廣西昌也, 伊東秀文, 柴田貴志, 有田奈佑香, 三溝雄史, 武知美佳, 奥村匡敏, 小倉光博, 篠崎和弘, 近藤智善, 塚原雅子, 河南憲子
Organizer
第55回日本神経学会学術大会
Place of Presentation
福岡国際センター
Year and Date
2014-05-24
Related Report
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[Presentation] 既存薬によるSOD1転写を標的とした筋委縮性側索硬化症新規治療法の開発2013
Author(s)
村上学, 井上治久, 月田香代子, 淺井康行, 饗庭一博, 天貝裕地, 山下博史, 植村健吾, 伊東秀文, 下川浩輝, 上杉志成, 中辻憲夫, 高橋良輔
Organizer
第54回日本神経学会総会学術大会
Place of Presentation
東京
Related Report
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[Presentation] Valosin Containing Protein遺伝子に新規変異を認めた筋萎縮性側索硬化症・Paget病の剖検例2012
Author(s)
綾木孝, 伊東秀文, 近藤孝之, 福島裕子, 井上健, 池本明人, 中野智, 藤田拓司, 山下博史, 猪原匡史, 松本理器, 川又純, 高橋良輔
Organizer
第53回 日本神経学会学術大会
Place of Presentation
東京国際フォーラム
Year and Date
2012-05-25
Related Report
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