Elucidation of the molecular mechanism caused by the neurotoxicity of OPTN mutations in ALS

• Project/Area Number: 23591246
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Hiroshima University
• Principal Investigator: MORINO Hiroyuki 広島大学, 原爆放射線医科学研究所, 助教 (10397953)
• Co-Investigator(Kenkyū-buntansha): KAWAKAMI Hideshi 広島大学, 原爆放射線医科学研究所, 教授 (70253060)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 神経分子病態 / 筋萎縮性側索硬化症 / 神経分子病態学

Research Abstract

We identified novel mutations of optineurin (OPTN) as a cause of amyotrophic lateral sclerosis (ALS), and OPTN is involved in various molecular mechanisms. We created OPTN knockout mice and knock-in mouse, and established mouse embryonic fibroblasts and ES cells for experiments with cultured cell lines. At this moment, we have not obtained a pathological phenotype, but pathological analysis revealed neuronal loss of the anterior horn of the spinal cord. There was not any significant change in the autophagy-associated molecules in the analysis using the MEF. However, it is indicated that OPTN plays an important role in cellular organelle regulation. We are aiming at revealing the detail of pathogenesis caused by OPTN mutation by iPS-derived neuron induced from the patient's fibroblast.

Research Products

• [Journal Article] A Japanese patient with familial ALS and a p.K510M mutation in the gene for FUS (FUS) resulting in the totally locked-in state (2014)
  • Author(s): Mochizuki Y, Kawata A, Maruyama H, Homma T, Watabe K, Kawakami H, Komori T, Mizutani T, Matsubara S
  • Journal Title: Neuropathology Volume: 34 Issue: 5 Pages: 504-509
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• [Journal Article] Neuropathological features of Japanese familial amyotrophic lateral sclerosis with p.N352S mutation in TARDBP (2014)
  • Author(s): Homma T, Nagaoka U, Kawata A, Mochizuki Y, Kawakami H, Maruyama H, Matsubara S, Komori T
  • Journal Title: Neuropathol Appl Neurobiol Volume: 40(2) Issue: 2 Pages: 231-6
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• [Journal Article] Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. (2014)
  • Author(s): Yagi R
  • Journal Title: Neurobiol Aging Volume: 35 Issue: 7 Pages: 1780.e1-1780.e5
  • DOI: 10.1016/j.neurobiolaging.2014.01.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient. (2014)
  • Author(s): Morino H, Miyamoto R, Ohnishi S, Maruyama H, Kawakami H
  • Journal Title: BMC Neurol Volume: 14 Issue: 1 Pages: 5-5
  • DOI: 10.1186/1471-2377-14-5
  • Peer Reviewed
• [Journal Article] Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia. (2014)
  • Author(s): Miyamoto R, Morino H, Yoshizawa A, Miyazaki Y, Maruyama H, Murakami N, Fukada K, Izumi Y, Matsuura S, Kaji R, Kawakami H.
  • Journal Title: J Neurol Sci. Volume: 337 Issue: 1-2 Pages: 219-223
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• [Journal Article] DYT6 in Japan-genetic screening and clinical characteristics of the patients. (2014)
  • Author(s): Miyamoto R, Koizumi H, Morino H, Kawarai T, Maruyama H, Mukai Y, Miyashiro A, Sako W, Izumi Y, Kawakami H, Kaji R.
  • Journal Title: Mov Disord. Volume: 29 Issue: 2 Pages: 278-280
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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
  • Journal Title: Neuropathology Volume: 34(1) Issue: 1 Pages: 58-63
  • DOI: 10.1111/neup.12049
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• [Journal Article] Exome sequencing reveals a novel ANO10 mutation in a Japanese patient with autosomal recessive spinocerebellar ataxia. (2014)
  • Author(s): Maruyama H, Morino H, Miyamoto R, Murakami N, Hamano T, Kawakami H.
  • Journal Title: Clin Genet. Volume: 85 Issue: 3 Pages: 296-297
  • DOI: 10.1111/cge.12140
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• [Journal Article] Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation. (2013)
  • 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.
  • Journal Title: Neuropathology Volume: 34 Issue: 1 Pages: 64-70
  • DOI: 10.1111/neup.12051
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• [Journal Article] Optineurin suppression causes neuronal cell death via NF-κB pathway. (2013)
  • Author(s): Akizuki M, Yamashita H, Uemura K, Maruyama H, Kawakami H, Ito H, Takahashi R.
  • Journal Title: J Neurochem Volume: 126(6) Issue: 6 Pages: 2230-41
  • DOI: 10.1111/jnc.12326
  • Peer Reviewed / Open Access
• [Journal Article] Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system (2013)
  • Author(s): Maruyama H, Morino H, Izumi Y, Noda K, Kawakami H
  • Journal Title: Am J Neurodegener Dis Volume: 2(1) Pages: 35-9
  • URL: http://www.ajnd.us/files/ajnd1212003.pdf
  • Peer Reviewed
• [Journal Article] Optineurin and amyotrophic lateral sclerosis (2013)
  • Author(s): Maruyama H, Kawakami H
  • Journal Title: Geriatr Gerontol Int Volume: 13(3) Issue: 3 Pages: 528-32
  • DOI: 10.1111/ggi.12022
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• [Journal Article] Oromandibular dystonia associated with SCA36. (2013)
  • Author(s): Miyashiro A, Sugihara K, Kawarai T, Miyamoto R, Izumi Y, Morino H, Maruyama H, Orlacchio A, Kawakami H, Kaji R.
  • Journal Title: Mov Disord. Volume: 28 Issue: 4 Pages: 558-559
  • DOI: 10.1002/mds.25304
  • Peer Reviewed
• [Journal Article] Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease. (2013)
  • Author(s): Izumi Y, Miyamoto R, Morino H, Yoshizawa A, Nishinaka K, Udaka F, Kameyama M, Maruyama H, Kawakami H
  • Journal Title: Neurology Volume: 80 Issue: 6 Pages: 600-601
  • DOI: 10.1212/wnl.0b013e3182815529
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• [Journal Article] Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system. (2013)
  • Author(s): Maruyama H, Morino H, Izumi Y, Noda K, Kawakami H
  • Journal Title: Am J Neurodegener Dis Volume: 2 Pages: 35-39
  • Peer Reviewed
• [Journal Article] The clinical characteristics of spinocerebellar ataxia 36: a study of 2121 Japanese ataxia patients (2012)
  • Author(s): Sugihara K, Maruyama H, Morino H, Miyamoto R, Ueno H, Matsumoto M, Kaji R, Kitaguchi H, Yukitake M, Higashi Y, Nishinaka K, Oda M, Izumi Y, Kawakami H
  • Journal Title: Mov Disord Volume: 27(9) Issue: 9 Pages: 1158-63
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• [Journal Article] Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene : a case series (2012)
  • Author(s): Ueno H, Kobatake K, Matsumoto M, Morino H, Maruyama H, Kawakami H
  • Journal Title: J Med Case Reports Volume: 5 Issue: 1 Pages: 573-573
  • DOI: 10.1186/1752-1947-5-573
  • Peer Reviewed
• [Journal Article] Optineurinの機能と病態 (2012)
  • Author(s): 川上秀史，吉澤明生
  • Journal Title: Medical Science Digest Volume: 38 Pages: 376-377
• [Journal Article] 筋萎縮性側索硬化症と遺伝子 (2012)
  • Author(s): 川上秀史
  • Journal Title: BIO Clinica Volume: 27 Pages: 1034-1037
• [Journal Article] Detection of large expansions in SCA8 using a fluorescent repeat-primed PCR assay (2011)
  • Author(s): Tanaka E, Maruyama H, Morino H, Kawakami H
  • Journal Title: Hiroshima J Med Sci Volume: 60(3) Pages: 63-6
  • NAID: 120005323966
  • URL: http://ir.lib.hiroshima-u.ac.jp/metadb/up/kiyo/AA00664312/HiroshimaJMedSci_60_63.pdf
  • Peer Reviewed
• [Journal Article] Homozygosity mapping on homozygosity haplotype analysis to detect recessive disease-causing genes from a small number of unrelated, outbred patients (2011)
  • Author(s): Hagiwara K, Morino H, Shiihara J, Tanaka T, Miyazawa H, Suzuki T, Kohda M, Okazaki Y, Seyama K, Kawakami H
  • Journal Title: PLoS One Volume: 6(9) Issue: 9 Pages: e25059-e25059
  • DOI: 10.1371/journal.pone.0025059
  • NAID: 120005300511
  • Peer Reviewed
• [Journal Article] Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation (2011)
  • Author(s): Ito H, Nakamura M, Komure O, Ayaki T, Wate R, Maruyama H, Nakamura Y, FujitaK, Kaneko S, Okamoto Y, Ihara M, Konishi T, Ogasawara K, Hirano A, Kusaka H, KajiR, Takahashi R, Kawakami H
  • Journal Title: Acta Neuropathologica Volume: 122 Issue: 2 Pages: 223-229
  • DOI: 10.1007/s00401-011-0842-y
  • Peer Reviewed
• [Journal Article] Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population (2011)
  • Author(s): Sugihara K, Maruyama H, Kamada M, Morino H, Kawakami H
  • Journal Title: Neurobiol Aging Volume: 32(10) Issue: 10 Pages: 1923.e9-1923.e10
  • DOI: 10.1016/j.neurobiolaging.2011.03.024
  • NAID: 120005308210
  • Peer Reviewed
• [Journal Article] The UCHL1 S18Y polymorphism and Parkinson's disease in a Japanese population (2011)
  • Author(s): Snapinn KW, Larson EB, Kawakami H, Ujike H, Borenstein AR, Izumi Y, Kaji R, Maruyama H, Mata IF, Morino H, Oda M, Tsuang DW, Yearout D, Edwards KL, Zabetian CP
  • Journal Title: Parkinsonism Relat Disord Volume: 17(6) Issue: 6 Pages: 473-5
  • DOI: 10.1016/j.parkreldis.2011.01.019
  • Peer Reviewed
• [Presentation] OPTN-ALS患者由来iPS細胞研究に向けて (2014)
  • Author(s): 川上秀史,平木啓子,大澤亮介,鈴木秀規,吉澤明生,倉持真人,森野豊之,和泉唯信,梶龍兒,加藤英政,丸山博文
  • Organizer: 平成25年度神経変性疾患に関する調査研究班分科班「病態に根ざしたALSの新規治療法開発」会議
  • Place of Presentation: 東京
  • Year and Date: 2014-01-17
• [Presentation] Novel C10orf2 mutations cause Perrault syndrome (2013)
  • Author(s): Kawakami H,Morino H,Miyamoto R,Maruyama H
  • Organizer: American Society of Human Genetics 63rd Annual Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2013-10-23
• [Presentation] 脊髄小脳失調症36型の臨床的特徴および日本人失調症患者2121人の病型別検討 (2013)
  • Author(s): 杉原勝宣,丸山博文,宮本亮介,森野豊之,上野弘貴,松本昌泰,北口浩史,雪竹基弘,東靖人,西中和人,織田雅也,和泉唯信,川上秀史
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-01
• [Presentation] VCP変異を認めたMND+IBMの臨床像と家族性ALSにおけるVCP変異の頻度 (2013)
  • Author(s): 鎌田正紀,池田和代,久米広大,浦井由光,出口一志,峠哲男,宮本亮介,杉原勝宣,森野豊之,丸山博文,川上秀史
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-31
• [Presentation] Perrault症候群の新規原因遺伝子 (2013)
  • Author(s): 森野豊之,宮本亮介,丸山博文,川上秀史
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-31
• [Presentation] 次世代シーケンサーで確認したSYNE1変異による脊髄小脳変性症の臨床像 (2013)
  • Author(s): 和泉唯信,宮本亮介,森野豊之,吉澤明生,西中和人,宇高不可思,亀山正邦,丸山博文,川上秀史
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-31
• [Presentation] AAV1を用いた変異Optineurin発現ALSモデルの作製 (2013)
  • Author(s): 川浪文,永井真貴子,早川英規,仁平友子,水野美邦,丸山博文,川上秀史,西山和利
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-30
• [Presentation] Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease (2013)
  • Author(s): Y Izumi, R Miyamoto, H Morino, A Yoshizawa, K Nishinaka, F Udaka, M Kameyama, H Maruyama, H Kawakami
  • Organizer: 65th American Academy of Neurology Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2013-03-20
• [Presentation] Novel C10orf2 mutations cause Perrault syndrome (2013)
  • Author(s): Kawakami H，Morino H，Miyamoto R，Maruyama H
  • Organizer: American Society of Human Genetics 63rd Annual Meeting
  • Place of Presentation: Boston (USA)
• [Presentation] Perrault症候群の新規原因遺伝子 (2013)
  • Author(s): 森野豊之，宮本亮介，丸山博文，川上秀史
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
• [Presentation] Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease. (2013)
  • Author(s): Y Izumi, R Miyamoto, H Morino, A Yoshizawa, K Nishinaka, F Udaka, M Kameyama, H Maruyama, H Kawakami
  • Organizer: 65th American Academy of Neurology Annual Meeting
  • Place of Presentation: San Diego (USA)
• [Presentation] Exome sequence identifies a novel MRE11 mutation in a patient with generalized myoclonic tremor (2012)
  • Author(s): R Miyamoto, H Morino, H Maruyama, Y Izumi, R Kaji, H Kawakami
  • Organizer: 62nd Annual Meeting of The American Society of Human Genetics
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2012-11-08
• [Presentation] SCA36の臨床的特徴 (2012)
  • Author(s): 杉原勝宣,丸山博文,宮本亮介,森野豊之,上野弘貴,北口浩史,雪竹基弘,東靖人,西中和人,織田雅也,和泉唯信,川上秀史
  • Organizer: 日本人類遺伝学会第57回大会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-27
• [Presentation] Exome sequencing identifies a novel MRE11 mutation in a patient with generalized myoclonic tremor (2012)
  • Author(s): 宮本亮介,森野豊之,丸山博文,和泉唯信,梶龍兒,川上秀史
  • Organizer: 日本人類遺伝学会第57回大会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-25
• [Presentation] ALS関連遺伝子のスクリーニング (2012)
  • Author(s): 杉原勝宣,宮本亮介,鎌田正紀,森野豊之,丸山博文,川上秀史
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-25
• [Presentation] 筋萎縮性側索硬化症の新規原因遺伝子optineurinの同定 (2012)
  • Author(s): 丸山博文,伊東秀文,川上秀史
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京(日本神経学会2011年度学会賞受賞者)
  • Year and Date: 2012-05-23
  • Invited
• [Presentation] 橋核の神経細胞の脱落とともに多数のFUS陽性構造物を広範囲な変性部位に認めたが、FUS/TLS遺伝子には変異を認めなかった家族性ALSの1例 (2012)
  • Author(s): 望月葉子,川田明広,新井誠,本間琢,渡部和彦,秋山治彦,川上秀史,小森隆司,水谷俊雄,松原四郎
  • Organizer: 第100回日本神経学会関東地方会
  • Place of Presentation: 東京
  • Year and Date: 2012-03-24
• [Presentation] 原因遺伝子からみたALS.シンポジウム「筋萎縮性側索硬化症(ALS)の病態解明に向けてー新薬開発の糸口と将来への期待」 (2012)
  • Author(s): 川上秀史
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-16
• [Presentation] 筋萎縮性側索硬化症の新規原因遺伝子optineurinの同定 (2012)
  • Author(s): 丸山博文，伊東秀文，川上秀史
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Optineurin変異による筋萎縮性側索硬化症の臨床経過および原因遺伝子の頻度 (2011)
  • Author(s): 丸山博文,和泉唯信,伊東秀文,森野豊之,阿部康二,杉原勝宣,宮本亮介,小畠敬太郎,川上秀史
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-11
• [Presentation] 好塩基性封入体を伴う成人発症運動ニューロン病におけるoptineurinの関与 (2011)
  • Author(s): 藤田賢吾,伊東秀文,金子鋭,中村正孝,和手麗香,川上秀史,日下博文
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-20
• [Presentation] FUS/TLS遺伝子変異を伴う家族性筋萎縮性側索硬化症(FALS)の臨床像の検討 (2011)
  • Author(s): 川田明広,平井健,長尾雅裕,清水俊夫,林秀明,磯崎英治,松原四郎,水谷俊雄,川上秀史,新井誠,秋山治彦
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] 常染色体劣性optineurin遺伝子変異による筋萎縮性側索硬化症 (2011)
  • Author(s): 鎌田正紀,和泉唯信,伊東秀文,香川聖子,工藤英治,丸山博文,川上秀史,梶龍兒
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] 筋萎縮性側索硬化症の原因遺伝子オプチニューリンの同定および頻度・臨床症状 (2011)
  • Author(s): 丸山博文,森野豊之,伊東秀文,和泉唯信,鎌田正紀,萩原弘一,阿部康二,小牟禮修,小畠敬太郎,上野弘貴,青木正志,日下博文,梶龍兒,川上秀史
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] Optineurin in ALS (2011)
  • Author(s): Hideshi Kawakami, Hirofumi Maruyama, Hidefumi Ito
  • Organizer: AAN-JSN Joint Symposium(日米神経学会合同シンポジウム)「ALS」第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] Optineurinは筋萎縮性側索硬化症の原因遺伝子である
  • Author(s): 丸山博文,森野豊之,和泉唯信,伊東秀文,川上秀史
  • Organizer: 第108回日本内科学会講演会
  • Place of Presentation: (東日本大震災のため誌上発表)
• [Remarks] 原爆放射線医科学研究所 分子疫学研究分野
  • URL: http://home.hiroshima-u.ac.jp/epidem/index.html
• [Remarks] 原爆放射線医科学研究所 分子疫学研究分野
  • URL: http://home.hiroshima-u.ac.jp/epidem/index.html
• [Remarks] 原爆放射線医科学研究所 分子疫学研究分野
  • URL: http://home.hiroshima-u.ac.jp/epidem/blosxom.cgi/Contents/introduction.htm