Polyglutamine diseases: investigation of transcriptional dystregulation

• Project/Area Number: 22240037
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: NUKINA Nobuyuki 独立行政法人理化学研究所, 構造神経病理研究チーム, チームリーダー (10134595)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥50,440,000 (Direct Cost: ¥38,800,000、Indirect Cost: ¥11,640,000); Fiscal Year 2012: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2011: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2010: ¥21,580,000 (Direct Cost: ¥16,600,000、Indirect Cost: ¥4,980,000)
• Keywords: ポリグルタミン病 / 転写 / NF-Y,TLS,sodium channel beta4 subunit / 転写因子 / ナトリウムチャンネルβサブユニット / 凝集体結合タンパク質 / ノックアウトマウス / 凝集体結合の蛋白質 / 凝集体結合蛋白質

Research Abstract

To investigate the pathological process of transcriptional abnormality in polyglutamine diseases, we examined the knockout mice of NF-YA and FUS/TLS, which are polyglutamine aggregates-interacting proteins, and the knockout mouse of sodium channel beta4 subunit, which is early downregulated gene in Huntington disease. We found unique pathology in those mice, which may relate to polyglutamine disease pathology.

Research Products

• [Journal Article] Goldin, A.L. & Chandy, K.G. Modulation of voltage-gated K+ channels by the sodium channel beta1 subunit (2012)
  • Author(s): Nguyen, H.M., Miyazaki, H., Hoshi, N., Smith, B.J., Nukina, N
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A Volume: 109 Pages: 18577-82
  • Peer Reviewed
• [Journal Article] ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT (2012)
  • Author(s): Bauer, P.O., Hudec, R., Goswami, A., Kurosawa, M., Matsumoto, G., Mikoshiba, K. & Nukina, N
  • Journal Title: Mol. Neurodegener Volume: 7 Pages: 43-43
  • Peer Reviewed
• [Journal Article] Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates (2012)
  • Author(s): Mitomi, Y., Nomura, T., Kurosawa, M., Nukina, N. & Furukawa, Y
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 34764-75
  • Peer Reviewed
• [Journal Article] N.V. Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates (2012)
  • Author(s): Ding, F., Furukawa, Y., Nukina, N. & Dokholyan
  • Journal Title: J. Mol. Biol Volume: 421 Pages: 548-60
  • Peer Reviewed
• [Journal Article] 【in vivo実験医学によるヒト疾患解明の最前線 生体イメージングとモデル動物を用いた研究戦略と臨床応用 疾患モデルと分子標的探索による治療薬開発】 ハンチントン病の治療法開発とモデルマウスを用いた評価 (2012)
  • Author(s): 紀嘉浩 & 貫名信行
  • Journal Title: 実験医学 Volume: 30 Pages: 349-356
• [Journal Article] 【神経筋疾患の分子標的治療開発】p62のリン酸化と選択的オートファジー (2012)
  • Author(s): 松本弦 & 貫名信行
  • Journal Title: BIO Clinica Volume: 27 Pages: 916-920
• [Journal Article] Modulation of voltage-gated K+ channels by the sodium channel beta1 subunit (2012)
  • Author(s): Nguyen, H.M.
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 109 Issue: 45 Pages: 18577-18582
  • DOI: 10.1073/pnas.1209142109
  • Peer Reviewed
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (2012)
  • Author(s): Klionsky, D. J.
  • Journal Title: Autophagy Volume: 8 Pages: 445-544
  • Peer Reviewed
• [Journal Article] ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT (2012)
  • Author(s): Bauer PO
  • Journal Title: Molecular Neurodegeneration Volume: 7(1) Issue: 1 Pages: 43-43
  • DOI: 10.1186/1750-1326-7-43
  • Peer Reviewed
• [Journal Article] Post-aggregation oxidation of mutant huntingtin controls the interactions between aggregates (2012)
  • Author(s): Mitomi, Y.
  • Journal Title: Journal of Biological Chemistry Volume: 287 Issue: 41 Pages: 34764-34775
  • DOI: 10.1074/jbc.m112.387035
  • Peer Reviewed
• [Journal Article] Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates (2012)
  • Author(s): Ding, F.
  • Journal Title: Journal of Molecular Biology Volume: 421 Issue: 4-5 Pages: 548-560
  • DOI: 10.1016/j.jmb.2011.12.029
  • Peer Reviewed
• [Journal Article] Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation (2011)
  • Author(s): Bauer, P.O., Hudec, R., Ozaki, S., Okuno, M., Ebisui, E., Mikoshiba, K. & Nukina, N
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 416 Pages: 13-7
  • Peer Reviewed
• [Journal Article] Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins (2011)
  • Author(s): Matsumoto, G., Wada, K., Okuno, M., Kurosawa, M. & Nukina, N
  • Journal Title: Mol. Cell Volume: 44 Pages: 279-89
  • Peer Reviewed
• [Journal Article] Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site (2011)
  • Author(s): Furukawa, Y., Kaneko, K. & Nukina, N
  • Journal Title: Biochim. Biophys. Acta Volume: 1812 Pages: 1577-83
  • Peer Reviewed
• [Journal Article] Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation (2011)
  • Author(s): Doi, H., Yoshida, K., Yasuda, T., Fukuda, M., Fukuda, Y., Morita, H., Ikeda, S., Kato, R., Tsurusaki, Y., Miyake, N., Saitsu, H., Sakai, H., Miyatake, S., Shiina, M., Nukina, N., Koyano, S., Tsuji, S., Kuroiwa, Y. & Matsumoto, N
  • Journal Title: Am J Hum Genet Volume: 89 Pages: 320-7
  • Peer Reviewed
• [Journal Article] Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties (2011)
  • Author(s): Furukawa, Y., Kaneko, K. & Nukina, N
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 27236-46
  • Peer Reviewed
• [Journal Article] A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions (2011)
  • Author(s): Furukawa, Y., Kaneko, K., Watanabe, S., Yamanaka, K. & Nukina, N
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 18664-72
  • Peer Reviewed
• [Journal Article] Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations (2011)
  • Author(s): Kino, Y., Washizu, C., Aquilanti, E., Okuno, M., Kurosawa, M., Yamada, M., Doi, H. & Nukina, N
  • Journal Title: Nucleic Acids Res Volume: 39 Pages: 2781-98
  • Peer Reviewed
• [Journal Article] Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation (2011)
  • Author(s): Bauer PO
  • Journal Title: Biochem Biophys Res Commun Volume: 16(1-2) Issue: 1-2 Pages: 13-7
  • DOI: 10.1016/j.bbrc.2011.10.096
  • Peer Reviewed
• [Journal Article] Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins (2011)
  • Author(s): Matsumoto, G., et al
  • Journal Title: Mol.Cell Volume: 44 Issue: 2 Pages: 279-289
  • DOI: 10.1016/j.molcel.2011.07.039
  • Peer Reviewed
• [Journal Article] A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions (2011)
  • Author(s): Furukawa, Y., et al
  • Journal Title: J Biol Chem Volume: 286 Issue: 21 Pages: 18664-18672
  • DOI: 10.1074/jbc.m111.231209
  • Peer Reviewed
• [Journal Article] Mechanism of ER Stress-Induced Brain Damage by IP(3) Receptor (2010)
  • Author(s): Higo, T., Hamada, K., Hisatsune, C., Nukina, N., Hashikawa, T., Hattori, M., Nakamura, T. & Mikoshiba, K
  • Journal Title: Neuron Volume: 68 Pages: 865-78
  • Peer Reviewed
• [Journal Article] Selection of behaviors and segmental coordination during larval locomotion is disrupted by nuclear polyglutamine inclusions in a new Drosophila Huntington's disease-like model (2010)
  • Author(s): Nishimura, Y., Yalgin, C., Akimoto, S., Doumanis, J., Sasajima, R., Nukina, N., Miyakawa, H., Moore, A.W. & Morimoto, T
  • Journal Title: J. Neurogenet Volume: 24 Pages: 194-206
  • Peer Reviewed
• [Journal Article] Transcription factor sequestration by polyglutamine proteins (2010)
  • Author(s): Yamanaka, T. & Nukina, N
  • Journal Title: Methods Mol. Biol Volume: 648 Pages: 215-29
  • Peer Reviewed
• [Journal Article] G. Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases (2010)
  • Author(s): Li, B., Hu, Q., Wang, H., Man, N., Ren, H., Wen, L., Nukina, N., Fei, E. & Wang
  • Journal Title: Cell Death Differ Volume: 17 Pages: 1773-84
  • Peer Reviewed
• [Journal Article] Mutation-dependent polymorphism of Cu,Zn-superoxide dismutase aggregates in the familial form of amyotrophic lateral sclerosis (2010)
  • Author(s): Furukawa, Y., Kaneko, K., Yamanaka, K. & Nukina, N
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 22221-31
  • Peer Reviewed
• [Journal Article] Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein (2010)
  • Author(s): Bauer, P.O., Goswami, A., Wong, H.K., Okuno, M., Kurosawa, M., Yamada, M., Miyazaki, H., Matsumoto, G., Kino, Y., Nagai, Y. & Nukina, N
  • Journal Title: Nat. Biotechnol Volume: 28 Pages: 256-63
  • Peer Reviewed
• [Journal Article] Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction (2010)
  • Author(s): Yamanaka, T., Tosaki, A., Miyazaki, H., Kurosawa, M., Furukawa, Y., Yamada, M. & Nukina, N
  • Journal Title: Hum. Mol. Genet Volume: 19 Pages: 2099-112
  • Peer Reviewed
• [Journal Article] Ranscht, B. & Isom, L.L. Functional reciprocity between Na+ channel Nav1.6 and {beta}1 subunits in the coordinated regulation of excitability and neurite outgrowth (2010)
  • Author(s): Brackenbury, W.J., Calhoun, J.D., Chen, C., Miyazaki, H., Nukina, N., Oyama, F
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A Volume: 107 Pages: 2283-8
  • Peer Reviewed
• [Journal Article] Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation (2010)
  • Author(s): Tateishi, T., Hokonohara, T., Yamasaki, R., Miura, S., Kikuchi, H., Iwaki, A., Tashiro, H., Furuya, H., Nagara, Y., Ohyagi, Y., Nukina, N., Iwaki, T., Fukumaki, Y. & Kira, J.I
  • Journal Title: Acta Neuropathol Volume: 119 Pages: 355-364
  • Peer Reviewed
• [Journal Article] The RNA-binding protein FUS/TLS is a common aggregate-interacting protein in polyglutamine diseases (2010)
  • Author(s): Doi, H., Koyano, S., Suzuki, Y., Nukina, N. & Kuroiwa, Y
  • Journal Title: Neurosci. Res Volume: 66 Pages: 131-3
  • Peer Reviewed
• [Journal Article] 【Protein Kinesisを解き明かす オルガネラの世界 細胞機能の制御と遺伝病発症・ウイルス感染のメカニズム】ポリグルタミン病のシャペロン介在性オートファジーを利用した新規治療法の開発 (2010)
  • Author(s): 貫名信行 & Bauer, P
  • Journal Title: 実験医学 Volume: 28 Pages: 2125-2128
• [Journal Article] 【SNARE複合体-膜融合の機構】 マイクロドメインスイッチング アミロイド前駆体蛋白質のマイクロドメイン依存性代謝調節とシンタキシン1 (2010)
  • Author(s): 櫻井隆, 樫山拓 & 貫名信行
  • Journal Title: 生体の科学 Volume: 61 Pages: 252-256
• [Journal Article] 【脳神経系の情報伝達と疾患 さまざまなシグナル伝達因子の異常が引き起こす精神疾患・発達障害・神経変性疾患のメカニズム】 神経疾患の細胞生物学 タンパク質分解系活性化による神経変性疾患治療 (2010)
  • Author(s): 伊野部智由 & 貫名信行
  • Journal Title: 実験医学 Volume: 28 Pages: 788-794
• [Journal Article] Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. (2010)
  • Author(s): Kino, Y, et al.
  • Journal Title: Nucleic Acids Res. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. (2010)
  • Author(s): Bauer, P.O., et al.
  • Journal Title: Nat.Biotechnol. Volume: 28 Pages: 256-263
  • Peer Reviewed
• [Journal Article] Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction. (2010)
  • Author(s): Yamanaka, T., et al.
  • Journal Title: Hum.Mol.Genet. Volume: 19 Pages: 2099-2112
  • Peer Reviewed
• [Presentation] Autophagic machinery for degrading the misfolded proteins (2012)
  • Author(s): Nukina, N
  • Organizer: The 6th International Symposium of Autophagy 2012 61
  • Place of Presentation: Nago, Japan
• [Presentation] Role of NF-Y transcription factor in neuronal cell maintenance and chaperone gene expression. EMBO (2012)
  • Author(s): Yamanaka, T., Tosaki, A., Kurosawa, M., Koike, M., Uchiyama, Y., Maity, S. & Nukina, N
  • Organizer: EMBL Symposia 2012: Quality Control - From Molecules to Organelles
  • Place of Presentation: Heiderberg, Germany
• [Presentation] ポリグルタミン病の病態と治療戦略 (2012)
  • Author(s): 貫名信行
  • Organizer: 第3回神経科学と構造生物学の融合研究会
  • Place of Presentation: 大阪(大阪大学蛋白質研究所)
• [Presentation] Autophagic machinery for degrading the misfolded proteins (2012)
  • Author(s): Nukina, N.
  • Organizer: The 6th International Symposium of Autophagy 2012
  • Place of Presentation: Nago, Japan
  • Invited
• [Presentation] Role of NF-Y transcription factor in neuronal cell maintenance and chaperone gene expression (2012)
  • Author(s): Yamanaka, T.
  • Organizer: EMBO | EMBL Symposia 2012: Quality Control - From Molecules to Organelles
  • Place of Presentation: Heiderberg, Germany
• [Presentation] Muscleblind proteins repress aberrant protein expression derived from expanded repeats (2011)
  • Author(s): Kino, Y., Washizu, C., Kurosawa, M., Oma, Y., Ishiura, S. & Nukina, N
  • Organizer: Internationa Myotonic Dystrophy Consortium -8 (IDMC-8)
  • Place of Presentation: Clearwater Beach, USA
• [Presentation] Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins (2011)
  • Author(s): Nukina, N
  • Organizer: Huntington's Disease WORLD CONGRESS 2011 24
  • Place of Presentation: Melbourne, Australia
• [Presentation] Enhancing the clearance of misfolded polyglutamine proteins (2011)
  • Author(s): Nukina, N
  • Organizer: 2011 Gordon Research Conferences on CAG Triplet Repeat Disorders
  • Place of Presentation: Lucca (Barga), Italy
• [Presentation] Phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins (2011)
  • Author(s): Matsumoto, G., Wada, K., Okuno, M., Kurosawa, M. & Nukina, N
  • Organizer: Cold Spring Harbor Laboratory 2011 Meeting on the Ubiquitin Family
  • Place of Presentation: Cold Spring Harbor, USA
• [Presentation] 凝集体形成からみた神経変性機序 (2011)
  • Author(s): 貫名信行
  • Organizer: 第52回日本神経学会学術大会 178
  • Place of Presentation: 名古屋(名古屋国際会議場)
• [Presentation] Using chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. (2010)
  • Author(s): Nukina, N.
  • Organizer: 第33回日本分子生物学会・第83回生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] The effects of ALS-linked mutations of FUS/TLS. BRI (2010)
  • Author(s): Kino, Y., Wahizu, C., Aquilanti, E., Okuno, M., Kurosawa, M., Yamada, M., Doi, H. & Nukina, N
  • Organizer: International Symposium 2010 "Current Understandings and Future Directions for ALS"
  • Place of Presentation: Niigata, Japan
• [Presentation] Requirement of phosphorylation of p62/SQSTM1 for autophagic degradation of polyubiquitinated proteins (2010)
  • Author(s): Matsumoto, G., Wada, K., Okuno, M. & Nukina, N
  • Organizer: The 3rd International Symposium on Protein Community 126
  • Place of Presentation: Nara, Japan
• [Presentation] Expanding world of autophagy: from molecular mechanisms to pathophysiological roles Using chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein (2010)
  • Author(s): 貫名信行
  • Organizer: 第33回日本分子生物学会・第83回生化学会大会合同大会 2PS12-6
  • Place of Presentation: 神戸(神戸ポートアイランド)
• [Presentation] ポリグルタミン病の治療法開発とモデルマウスを用いた評価 (2010)
  • Author(s): 貫名信行
  • Organizer: 第3回疾患モデルシンポジウム"精神神経疾患のモデル動物とその応用
  • Place of Presentation: 東京(中央大学駿河台記念会館)
• [Presentation] Search for neuronal circuit specific changes in polyglutamine diseases (2010)
  • Author(s): Nukina, N
  • Organizer: Kick of symposium of Scientific Research on Innovative Area "Foundation of Synapse and neurocircuit Pathology"
  • Place of Presentation: 東京(東京医科歯科大学)
• [Presentation] ポリグルタミン封入体結合蛋白としてのFUS/TLS (2010)
  • Author(s): 貫名信行
  • Organizer: 第51回日本神経学会総会 Vol. 50 臨床神経学
  • Place of Presentation: 東京(東京国際フォーラム)
• [Presentation] Novel gene therapy for polyglutamine diseases to selectively degrade the pathogenic protein (2010)
  • Author(s): Nukina, N., Bauer, P.O., Goswami, A., Wong, H.K., Okuno, M., Kurosavva, M., Yamada, M., Miyazaki, H., Matsumoto, G., Kino, Y. & Nagai, Y
  • Organizer: Japan society of Gene Therapy The 16th Annual Meeting 2010 (第16回日本遺伝子治療学会年次学術集会)
  • Place of Presentation: 宇都宮(栃木県総合文化センター)
• [Book] ハンチントン病モデルマウス. 脳・神経疾患.疾患モデルの作成と利用 (ed. 三品昌美) (2011)
  • Author(s): 紀嘉浩, 黒沢大 & 貫名信行
  • Publisher: エル・アイ・シー, 東京