Integrated research of polyglutamine disease and ALS/FTLD by analysis of UBQLN2

• Project/Area Number: 25293207
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Yokohama City University
• Principal Investigator: TANAKA Fumiaki 横浜市立大学, 医学(系)研究科(研究院), 教授 (30378012)
• Co-Investigator(Kenkyū-buntansha): DOI Hiroshi 横浜市立大学, 医学部, 講師 (10326035) ; KOYANO Shigeru 横浜市立大学, 医学部, 准教授 (50315818) ; TANAKA Ken-ichi 横浜市立大学, 医学部, 助教 (50722881)
• Co-Investigator(Renkei-kenkyūsha): NUKINA Nobuyuki 順天堂大学, 医学研究科, 客員教授 (10134595)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2015: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
• Keywords: ALS / ポリグルタミン病 / UBQLN2 / 脳神経疾患 / 神経科学

Outline of Final Research Achievements

We aimed to elucidate the role of UBQLN2 in neurodegeneration of ALS/FTLD and polyglutamine disease. Using mass spectrometry equipment we tried to identify molecules that exhibit differential binding affinity for wild-type and mutant UBQLN2 causing ALS/FTLD. As a result, Hsc71 was identified as one of the proteins showing reduced binding affinity for mutant UBQLN2. Further, we found that binding with Hsc71 depends on PXX domain of UBQLN2. In addition, we created the total and neuron-specific UBQLN2 knockout mice by mating Ubqln2 flox/flox mice with Actb-Cre mice and the Tubb3-Cre mice, respectively.

Research Products

• [Journal Article] Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort (2016)
  • Author(s): Ryoichi Nakamura, Jun Sone, Naoki Atsuta, Genki Tohnai, Hazuki Watanabe, Daichi Yokoi, Masahiro Nakatochi, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe.
  • Journal Title: Neurobiology of Aging Volume: 39 Pages: 219-219
  • DOI: 10.1016/j.neurobiolaging.2015.11.030
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association of multiple sclerosis with lateral olfactory tract usher substance (LOTUS), a possible endogenous inhibitor of axonal degeneration (2015)
  • Author(s): Takahashi K, Takei K, Tanaka F
  • Journal Title: Clin Exp Neuroimmunol Volume: 6 Issue: S1 Pages: 64-69
  • DOI: 10.1111/cen3.12272
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation (2015)
  • Author(s): Kunii M, Doi H, Higashiyama Y, Kugimoto C, Ueda N, Hirata J, Tomita-Katsumoto A, Kashikura-Kojima M, Kubota S, Taniguchi M, Murayama K, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N, Tanaka F.
  • Journal Title: J Hum Genet Volume: 60 Issue: 4 Pages: 187-191
  • DOI: 10.1038/jhg.2015.7
  • NAID: 40020433141
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative analysis of intraneuronal transport in human iPS neurons (2015)
  • Author(s): Nakamura H, Yamashita N, Kanamaru Y, Tachibana T, Sekino Y, Chen S, Gotoh T, Tanaka F, Goshima Y
  • Journal Title: J Pharmacol Sci Volume: 128 Issue: 4 Pages: 170-178
  • DOI: 10.1016/j.jphs.2015.06.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis (2015)
  • Author(s): Takahashi K, Kurihara Y, Suzuki Y, Goshima Y, Tanaka F, Takei K.
  • Journal Title: JAMA Neurol Volume: 72 Issue: 2 Pages: 176-179
  • DOI: 10.1001/jamaneurol.2014.3613
  • Peer Reviewed / Open Access
• [Journal Article] Neuropathological staging of spinocerebellar ataxia type 2 by semiquantitative 1C2-positive neuron typing Nuclear translocation of cytoplasmic 1C2 underlies disease progression of spinocerebellar ataxia type 2. (2014)
  • Author(s): Koyano S, Yagishita S, Kuroiwa Y, Tanaka F, Uchihara T.
  • Journal Title: Brain Pathol Volume: 26 Issue: 6 Pages: 599-606
  • DOI: 10.1111/bpa.12146
  • Peer Reviewed
• [Journal Article] Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation (2014)
  • Author(s): Doi H, Ushiyama M, Baba T, Tani K, Shiina M, Ogata K, Miyatake S, Yuzawa YF, Tsuji S, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ikeda S, Tanaka F, Matsumoto N, Yoshida K
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 7132-7132
  • DOI: 10.1038/srep07132
  • NAID: 120007100602
  • Peer Reviewed / Open Access
• [Journal Article] 神経細胞変性のメカニズム「蛋白質凝集と神経変性」 (2014)
  • Author(s): 土井 宏, 田中章景
  • Journal Title: BRAIN MEDICAL Volume: 26 Pages: 73-79
• [Journal Article] Increased number of astrocytes and macrophages/microglial cells in the corpus callosum in amyotrophic lateral sclerosis (2013)
  • Author(s): Sugiyama M, Takao M, Hatsuta H, Funabe S, Ito S, Obi T, Tanaka F, Kuroiwa Y, Murayama S.
  • Journal Title: Neuropathology Volume: 34 Issue: 6 Pages: 591-9
  • DOI: 10.1111/neup.12027
  • Peer Reviewed
• [Journal Article] RNP2 of RNA recognition motif 1 plays a central role in the aberrant modification of TDP-43. (2013)
  • Author(s): Takagi S, Iguchi Y, Katsuno M, Ishigaki S, Ikenaka K, Fujioka Y, Honda D, Niwa J, Tanaka F, Watanabe H, Adachi H, Sobue G.
  • Journal Title: PLoS One. Volume: 28 Issue: 6 Pages: e66966-e66966
  • DOI: 10.1371/journal.pone.0066966
  • Peer Reviewed
• [Journal Article] Ablation of Keratan Sulfate Accelerates Early Phase Pathogenesis of ALS. (2013)
  • Author(s): Kenichi Hirano, Tomohiro Ohgomori, Kazuyoshi Kobayashi, Fumiaki Tanaka, Tomohiro Matsumoto, Takamitsu Natori, Yukihiro Matsuyama, Kenji Uchimura, Kazuma Sakamoto, Hideyuki Takeuchi, Akihiro Hirakawa, Akio Suzumura, Gen Sobue, Naoki Ishiguro, Shiro Imagama, Kenji Kadomatsu
  • Journal Title: PLoS ONE Volume: 8(6) Issue: 6 Pages: e66969-e66969
  • DOI: 10.1371/journal.pone.0066969
  • NAID: 120005946841
  • Peer Reviewed
• [Journal Article] dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration (2013)
  • Author(s): Ikenaka K
  • Journal Title: PLoS One Volume: 8 Issue: 2 Pages: e54511-e54511
  • DOI: 10.1371/journal.pone.0054511
  • Peer Reviewed
• [Presentation] 孤発性筋萎縮性側索硬化症におけるMatrin3の病理学的検討 (2015)
  • Author(s): 多田 美紀子、土井 宏、児矢野 繁、田中 章景
  • Organizer: 第56回日本神経病理学会総会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県福岡市東区）
  • Year and Date: 2015-06-03
• [Presentation] SCA2病変におけるTDP-43細胞内局在 (2015)
  • Author(s): 児矢野 繁、多田 美紀子、柳下 三郎、内原 俊記，田中 章景
  • Organizer: 第56回日本神経病理学会総会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県福岡市東区）
  • Year and Date: 2015-06-03
• [Presentation] Late-onset spastic ataxia phenotype related to a novel homozygous DDHD2 mutation (2015)
  • Author(s): 土井 宏、吉田 邦広、牛山 雅夫、谷 佳津子、松本 直通、田中 章景
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県新潟市中央区）
  • Year and Date: 2015-05-20
• [Presentation] RNA病からみた認知症関連疾患 C9orf72遺伝子変異と前頭側頭型認知症 (2014)
  • Author(s): 田中章景
  • Organizer: 第33回日本認知症学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-29 – 2014-12-01
  • Invited
• [Presentation] Analysis of major amyotrophic lateral sclerosis genes in Japan (2014)
  • Author(s): Nakamura R, Sone J, Atsuta N, Watanabe H, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno K, Tanaka F, Izumi Y, Morita M, Ogaki K, Taniguchi A, Aiba A, Mizoguchi K, Okamoto K, Hasegawa K, Aoki M, Kawata A, Abe K, Oda M, Konagaya M, Imai T, Nakagawa M, Tsuji S, Kaji R, Nakano I, Sobue G
  • Organizer: 64th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] ALSの呼吸機能評価における横隔膜エコーと横隔神経M波振幅の組み合わせの有用性 (2014)
  • Author(s): 釘本千春、岩橋幸子、小林絵礼奈、斎藤麻美、山崎舞子、東山雄一、上木英人, 田中章景
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] 運動ニューロン特異的TDP-43ノックアウトマウスの病理学的検討 (2013)
  • Author(s): 井口洋平, 勝野雅央, 丹羽淳一, 高木伸之介, 山中宏二, 三澤日出巳, 高橋良輔, 佐々木彰一, 田中章景, 祖父江元
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] dynactin-1ノックアウトによる孤発性ALSモデルマウスの作成と病態解析 (2013)
  • Author(s): 河合香里, 池中建介, 勝野雅央, 井口洋平, 勝又 竜, 田中章景, 祖父江元
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] 熱ショック因子1は球脊髄性筋萎縮症の運動神経変性を抑える (2013)
  • Author(s): 近藤直英, 勝野雅央, 足立弘明, 南山 誠, 土井英樹, 松本慎二郎, 宮崎 雄, 飯田 円, 中辻秀朗, 藤内玄規, 石垣診祐, 藤岡祐介, 渡辺宏久, 田中章景, 祖父江元
  • Organizer: 第36回日本神経科学大会 Neuro 2013
  • Place of Presentation: 国立京都国際会館（京都府京都市左京区）