Elucidation of causative mechanism of amyotrophic lateral sclerosis via abnormality of methylation of TLS and development of its therapeutics.

• Project/Area Number: 23659461
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Saitama Medical University
• Principal Investigator: KUROKAWA Riki 埼玉医科大学, 医学部, 教授 (70170107)
• Co-Investigator(Renkei-kenkyūsha): MATSUSITA Akio 埼玉医科大学, 医学部, 客員講師 (50402269) ; OGAWA Sumito 東京大学, 医学部附属病院, 講師 (20323579)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 酵素 / 遺伝子 / 核酸 / 生体分子 / 発現制御

Research Abstract

RNA-binding protein TLS has been reported as a causative gene for amyotrophic lateral sclerosis (ALS). At the ALS-mutant TLS lost binding of protein arginine N-methyltransferase 5 (PRMT 5). Then, we hypothesize that the mutated TLS should cause ALS through formation of the insoluble aggregates induced by abnormality of binding of proteins elicited with deletion of arginine-specific methylation. Specific aim of the study is to prove the hypothesis and generate an “RNA ligand” to recover the binding of PRMT5 to TLS. Then, we have shown novel mechanism of arginine-methylation of TLS and attained significant progress in generating the RNA ligand

Research Products

• [Journal Article] Regulatjon of Telomere Length by G-Quadruplex Telomere DNA- and T ERRA・Binding Protain TLSiFUS. (2013)
  • Author(s): 高濱 謙太朗
  • Journal Title: Chemistry & Biology誌 Volume: 20 Issue: 3 Pages: 341-350
  • DOI: 10.1016/j.chembiol.2013.02.013
  • Peer Reviewed
• [Journal Article] RNAのメチル化も遺伝子発現を制御していた (2013)
  • Author(s): 黒川 理樹
  • Journal Title: 実験医学 Volume: Vol.31 Pages: 58-59
• [Journal Article] Structure of noncoding RNA is a determinant of function of RNA binding proteins in transcriptional regulation. (2012)
  • Author(s): Oyoshi, T., and Kurokawa, R.
  • Journal Title: Cell & Bioscience Volume: 2 Issue: 1 Pages: 1-1
  • DOI: 10.1186/2045-3701-2-1
  • Peer Reviewed
• [Journal Article] 小分子非コードpiRNAとDNAメチル化が長期記憶を誘導する (2012)
  • Author(s): 黒川 理樹
  • Journal Title: 実験医学 Volume: Vol.30 Pages: 1925-1926
• [Journal Article] 非コードRNAとポリコームメチル化が核局在を決め遺伝子を制御する (2012)
  • Author(s): 黒川 理樹
  • Journal Title: 実験医学 Volume: Vol.30 Pages: 458-459
• [Journal Article] Loop Lengths of G-Quadruplex Structures Affect the G-Quadruplex DNA Binding Selectivity of the RGG Motif in Ewing's Sarcoma. (2011)
  • Author(s): Takahama, K., Sugimoto, C., Arai, S., Kurokawa, R., and Oyoshi, T.
  • Journal Title: Biochemistry Volume: 50 Issue: 23 Pages: 5369-5378
  • DOI: 10.1021/bi2003857
  • Peer Reviewed
• [Journal Article] Identification of Ewing's sarcoma protein as a G-quadruplex DNA- and RNA-binding protein (2011)
  • Author(s): Takahama, K., Kino, K., Arai, S., Kurokawa, R., and Oyoshi, T.
  • Journal Title: FEBS Journal Volume: 278 Issue: 6 Pages: 988-998
  • DOI: 10.1111/j.1742-4658.2011.08020.x
  • Peer Reviewed
• [Journal Article] TLS and PRMT1 synergistically coactivate transcription at the survivin promoter through TLS arginine methylation (2011)
  • Author(s): Du, K., Arai, S., Kawamura, T., Matsushita, A., and Kurokawa, R.
  • Journal Title: BBRC Volume: 404 Issue: 4 Pages: 991-996
  • DOI: 10.1016/j.bbrc.2010.12.097
  • Peer Reviewed
• [Journal Article] Long Noncoding RNA as a Regulator for Transcription. In: Ugarkovic, D.(ed) Long Non-Coding RNAs (2011)
  • Author(s): Kurokawa, R.
  • Journal Title: Progress in Molecular and Subcellular Biology 51 Volume: 2 Pages: 29-41
  • DOI: 10.1007/978-3-642-16502-3_2
  • ISBN: 9783642165016, 9783642165023
  • Peer Reviewed
• [Journal Article] FUS/TLS構造と機能からALS病態をみる (2011)
  • Author(s): 黒川 理樹
  • Journal Title: 実験医学 Volume: Vol.29 Pages: 1032-1034
• [Journal Article] 遺伝子発現は転写と翻訳で制御されるが、どちらが主役か？ (2011)
  • Author(s): 黒川 理樹
  • Journal Title: 実験医学 Volume: Vol.29 Pages: 2258-2259
• [Journal Article] 新生RNAのDeep sequencingで明らかになる真核ゲノムの転写動態 (2011)
  • Author(s): 黒川 理樹
  • Journal Title: 実験医学 Volume: Vol.29 Pages: 1263-1264
• [Journal Article] a new candidate gene for senile osteoporosis, acts as a molecular switch promoting osteoblast differentiation (2010)
  • Author(s): Tokuzawa, Y., Yagi, K., Yamashita ,Y., Nakachi, Y., Nikaido, I., Bono, H., Ninomiya, Y., Kanesaki-Yatsuka, Y., Akita, M., Motegi, H., Wakana, S., Noda, T., Sablitzky, F., Arai, S., Kurokawa, R., Fukuda, T., Katagiri, T.Schonbach, C., Suda, T., Mizuno, Y., and Okazaki, Y. Id4
  • Journal Title: PLoS Genet Volume: 6
  • Peer Reviewed
• [Presentation] 長鎖非コード RNA 機能の分子機構-核酸医薬の可能性 (2012)
  • Author(s): 黒川 理樹
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡県福岡市
  • Year and Date: 2012-12-12
• [Presentation] Long noncoding RNA as an epigenetic regulatory factor (2012)
  • Author(s): Kurokawa, R
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2012-09-20
• [Presentation] Long noncoding RNA, a counterpart of microRNA, works as a transcriptional regulator. Is lncRNA a potential target for nucleic acid medicine? (2012)
  • Author(s): Kurokawa, R
  • Organizer: 第4回日本 RNAi 研究会
  • Place of Presentation: 広島県広島市
  • Year and Date: 2012-08-30
• [Presentation] Promoter-associated noncoding RNA and Arginine-specific Methylation of RNA-binding protein TLS. (2012)
  • Author(s): Kurokawa, R.
  • Organizer: Keystone Symposia
  • Place of Presentation: Utah, USA.
  • Year and Date: 2012-04-04
• [Presentation] 長鎖非コードRNA機能の分子機構-核酸医薬の可能性 (2012)
  • Author(s): 黒川 理樹
  • Organizer: 第35回日本分子生物学会年会 ワークショップ主催
  • Place of Presentation: 福岡県福岡市
  • Invited
• [Presentation] エピゲノム制御因子としての長鎖非コードRNA (2012)
  • Author(s): 黒川 理樹
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 北海道札幌市
  • Invited
• [Presentation] マイクロRNAのカウンターパート長鎖非コードRNAは転写を制御する-LncRNAは核酸医薬のシードになりうるか？ (2012)
  • Author(s): 黒川 理樹
  • Organizer: 第4回日本RNAi研究会
  • Place of Presentation: 広島県広島市
  • Invited
• [Presentation] Promoter-associated noncoding RNA and Arginine-specific Methylation of RNA-binding protein TLS. (2012)
  • Author(s): Kurokawa, R.
  • Organizer: Keystone Symposia
  • Place of Presentation: Snowbird, Utah, USA
  • Invited
• [Presentation] 長鎖非コード RNA とエピゲノム制御 (2011)
  • Author(s): 黒川 理樹
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2011-12-16
• [Presentation] TLS-CHOP, an Oncogenic Fusion Product in Myxoid Liposarcoma, Attenuates Cell Adhesion Ability through Down-Regulation of Integrin α5β1. (2011)
  • Author(s): Kurokawa, R
  • Organizer: ENDO (The Endocrine Society) 2011
  • Place of Presentation: Boston, USA
  • Year and Date: 2011-06-06
• [Presentation] 長鎖非コードRNAとエピゲノム制御 (2011)
  • Author(s): 黒川 理樹
  • Organizer: 第34回日本分子生物学会年会(招待講演)
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] TLS-CHOP, an Oncogenic Fusion Product in Myxoid Liposarcoma, Attenuates Cell Adhesion Ability through Down-Regulation of Integrin α5β1. (2011)
  • Author(s): Arai, S.
  • Organizer: ENDO 2011
  • Place of Presentation: Boston Convention & Exhibition Center(Boston, USA)
• [Book] Springer Berlin Heidelberg, Generation of Functional Long Noncoding RNA Through Transcription and Natural Selection. (2012)
  • Author(s): Kurokawa, R
  • Publisher: In: Mallick, B. (eds.) Regulatory RNAs
• [Book] Springer New York,Promoter-Associated Noncoding RNA from the CCND1 Promoter. (2012)
  • Author(s): Song, X., Wang, X., Arai, S., and Kurokawa, R
  • Publisher: In: Vancura, A. (ed) Transcriptional Regulation: Methods and Protocols, Methods in Molecular Biology 809
• [Book] Transcriptional Regulation. Promoter-Associated Noncoding RNA from the CCND1 Promoter. In: Vancura, A. (ed) (2012)
  • Author(s): Song, X.
  • Publisher: Humana Press
• [Book] RNA Infrastructure and Networks. Promoter-Associated Long Noncoding RNAs Repress Transcription Through an Rna Binding Protein TLS. In: Collins, LJ.(ed) (2011)
  • Author(s): Kurokawa, R.
  • Publisher: Landes Biosciences
• [Remarks]
  • URL: http://www.saitama-med.ac.jp/genome/
• [Remarks] 埼玉医科大学ゲノム医学研究センター
  • URL: http://www.saitama-med.ac.jp/genome/
• [Remarks] 埼玉医科大学ゲノム医学研究センター遺伝子構造機能部門
  • URL: http://space.geocities.jp/idensikouzou/index.html#
• [Remarks]
  • URL: http://space.geocities.jp/idensikouzou/index.html
• [Patent(Industrial Property Rights)] 抗ＴＬＳモノクローナル抗体及びその製造方法、ハイブリドーマ及びその製造方法、並びに抗ＴＬＳモノクローナル抗体含有組成物 (2013)
  • Inventor(s): 黒川 理樹
  • Industrial Property Rights Holder: 黒川 理樹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-099962
  • Filing Date: 2013-05-10
• [Patent(Industrial Property Rights)] 抗 TLS モノクローナル抗体及びその製造方法、ハイブリドーマ及びその製造方法、並びに抗 TLS モノクローナル抗体含有組成物 (2012)
  • Inventor(s): 黒川 理樹
  • Industrial Property Rights Holder: 黒川 理樹
  • Industrial Property Number: 2013-009996
  • Filing Date: 2012-05-10