Molecular pathogenesis of myotonic dystrophy in the central nervous system

• Project/Area Number: 23591258
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Hyogo Medical University
• Principal Investigator: TAKASHI Kimura 兵庫医科大学, 医学部, 講師 (20441264)
• Co-Investigator(Kenkyū-buntansha): YOSHIKAWA Hiroo 兵庫医科大学, 教授 (90273680) ; KUBO Shuji 兵庫医科大学, 准教授 (10441320)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2011: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: 筋強直性ジストロフィー / 中枢神経症状 / スプライシング異常 / MBNL1/2 / 国際情報交換 / 米国、フロリダ / 米国、フロリダ大学 / 国際情報交流

Research Abstract

We showed that nuclear sequestration of alternative splicing factors, muscleblind-like 1 (MBNL1) and MBNL2 explains splicing defects observed in human myotonic dystrophy type 1 (DM1) brain and the contribution of MBNL2 is greater than that of MBNL1. We found similar splicing defects in frontal cortex, temporal cortex, and hippocampus, but not in cerebellum from DM1 patients. It is probable that the shortest CTG repeat expansion could contribute to the lack of splicing defects in DM1 cerebellum. Also, the less expression of DMPK protein might be related with the fact that pathological abnormalities were not found in the DM1 cerebellum.

Research Products

• [Journal Article] Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy (2012)
  • Author(s): Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti MM, Xia G, Kumar A, Ashizawa T, Clark HB, Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Gomes-Pereira M, Gourdon G, Sakai N, Nishino S, Foster TC, Ares M, Jr., Darnell RB, Swanson MS
  • Journal Title: Neuron Volume: 75(3) Pages: 437-50
  • Peer Reviewed
• [Journal Article] T. Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain (2012)
  • Author(s): Suenaga K, Lee KY, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Du H, Ares M, Jr., Swanson MS, Kimura
  • Journal Title: PLoS One Volume: 7(3)
  • Peer Reviewed
• [Journal Article] Muscleblind-like 2 mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. (2012)
  • Author(s): Charizanis K, Lee K-Y, Batra R, 中略 Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Gomes-Pereira M, Gourdon G, Sakai N, Nishino S, Ares Jr M, Darnell RB, Swanson M.
  • Journal Title: Neuron Volume: 75 Issue: 3 Pages: 467-450
  • DOI: 10.1016/j.neuron.2012.05.029
  • Peer Reviewed
• [Journal Article] Muscleblind-like 1 Knockout Mice Reveal Novel Splicing Defects in the Myotonic Dystrophy Brain (2012)
  • Author(s): Suenaga K, Lee KY, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Du H, Ares M Jr, Swanson MS, Kimura T
  • Journal Title: PLoS One Volume: 7(3) Issue: 3 Pages: e33218-e33218
  • DOI: 10.1371/journal.pone.0033218
  • Peer Reviewed
• [Presentation] Altered Splicing of Cardiac Sodium Channel Might Be Responsible for Cardiac Conduction Defects in Myotonic Dystrophy (2013)
  • Author(s): Yosuke KOKUNAI, Hideki ITOH, Yoshihiro KINO, Moyi LI, Masayuki NAKAMORI, Takashi KIMURA, Tsuyoshi MATSUMURA, Harutoshi, FUJIMURA, Nobuyuki NUKINA, Hideki MOCHIZUKI, Saburo SAKODA, Minoru HORIE, Shouichi ICHIURA, Keiji IMOTO, Maurice SWANSON, Nicolas CHARLET BERGUERAND, Masanori TAKAHASHI
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: San Sebastian, Spain
  • Year and Date: 2013-10-17
• [Presentation] he distribution of splicing defects in the Myotonic Dystrophy type 1 brain (2013)
  • Author(s): Takashi KIMURA, Koichi SUENAGA, Masayuki NAKAMORI, Tsuyoshi MATSUMURA, Masanori TAKAHASHI, Harutoshi FUJIMURA, Kenji JINNAI, Hiroo YOSHIKAWA. T
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: San Sebastian, Spain
  • Year and Date: 2013-10-17
• [Presentation] 筋強直性ジストロフィー症における中枢神経スプライシング異常の局在性の検討 (2013)
  • Author(s): 末永浩一、木村卓、中森雅之、高橋正紀、松村剛、藤村晴俊、陣内研二、芳川浩男
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-29
• [Presentation] 筋強直性ジストロフィー症における中枢神経スプラシング異常およびその分子機序の解明 (2012)
  • Author(s): 末永浩一、木村卓、Kuang-Yung Lee、中森雅之、高橋正紀、藤村晴俊、陣内研二、久保秀司、玉置(橋本)知子、Manuel Ares Jr.、Maurice S. Swanson、芳川浩男
  • 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] 筋強直性ジストロフィー症における中枢神経スプライシング異常およびその分子機序の解明 (2012)
  • Author(s): 末永浩一，木村卓，Lee K-Y ,中森雅之，高橋正紀，藤村晴俊，陣内研二，久保秀司，玉置（橋本）知子，Manuel A, Maurice S,芳川浩男
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] Muscleblind-like 2 knockout mice : a model for splicing alterations and neurological changes in the DM brain (2011)
  • Author(s): Charizanis K, Lee K-Y, Scotti MM, Xia G, Shiue L, Cline MS, Ares M Jr, Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Swanson MS
  • Organizer: 8th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Clearwater, USA
  • Year and Date: 2011-12-02
• [Presentation] Muscleblind-like 1 Knockout Mice Reveal Novel Splicing Defects in the Myotonic Dystrophy Brain (2011)
  • Author(s): Kimura T, Lee K-Y, Suenaga K, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Du H, Ares M Jr., Swanson MS
  • Organizer: 8th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Clearwater, USA
  • Year and Date: 2011-12-02
• [Presentation] Altered splicing of cardiac sodium channel in heart muscles of myotonic dystrophy type 1 (2011)
  • Author(s): Kokunai Y, Kino Y, Moyi L, Itoh H, Nakamori M, Kimura T, Matsumura T, Fujimura H, Nukina N, Sakoda S, Horie M, Imoto K, Ishiura S, Swanson MS, Takahashi MP
  • Organizer: 8th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Clearwater, USA
  • Year and Date: 2011-12-01
• [Presentation] 筋強直性ジストロフィー症における中枢神経スプラシング異常およびその分子機序の解明 (2011)
  • Author(s): 末永浩一、木村卓、Kuang-Yung Lee、中森雅之、高橋正紀、松村到、藤村晴俊、陣内研二、久保秀司、玉置(橋本)知子、Manuel Ares Jr., Maurice S. Swanson,芳川浩男
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-19
• [Presentation] 筋強直性ジストロフィー症におけるスプライシング異常およびその分子機序の解明 (2011)
  • Author(s): 末永浩一，木村卓，Lee K，中森雅之，高橋正紀，松村剛，藤村晴俊，陣内研二，久保秀司，玉置（橋本）知子，Ares M, Swanson MS, 芳川浩男
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] Muscleblind-like 2 knockout mice: a model for splicing alterations and neurological changes in the DM brain. (2011)
  • Author(s): Charizanis K, Lee K-Y, Scotti MM, Xia G, Shiue L, Cline MS, Ares M, Jr., Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Swanson MS.
  • Organizer: 8th international myotonic dystrophy consortium meeting (IDMC-8)
  • Place of Presentation: 米国、クリアウォーター
• [Presentation] Muscleblind-like 1 Knockout Mice Reveal Novel Splicing Defects in the Myotonic Dystrophy Brain. (2011)
  • Author(s): Kimura T, Lee K-Y, Suenaga K, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Du H, Ares M, Jr., Swanson MS.
  • Organizer: 8th international myotonic dystrophy consortium meeting (IDMC-8)
  • Place of Presentation: 米国、クリアウォーター
• [Presentation] Altered splicing of cardiac sodium channel in heart muscles of myotonic dystrophy type 1 (2011)
  • Author(s): Kokunai Y, Kino Y, Moyi L, Itoh H, Nakamori M, Kimura T, Matsumura T, Fujimura H, Nukina N, Sakoda S, Horie M, Imoto K, Ishiura S, Swanson MS, Takahashi MP.
  • Organizer: 8th international myotonic dystrophy consortium meeting (IDMC-8)
  • Place of Presentation: 米国、クリアウォーター
• [Presentation] 筋強直性ジストロフィー心筋におけるNaチャネルのスプライシング異常. (2011)
  • Author(s): 穀内洋介, 中森雅之, 木村卓, 松村剛, 藤村晴俊, 佐古田三郎, 高橋正紀
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] Altered Splicing of Cardiac Sodium Channel Might Be Responsible for Cardiac Conduction Defects in Myotonic Dystrophy.
  • Author(s): Yosuke KOKUNAI, Hideki ITOH, Yoshihiro KINO, Moyi LI, Masayuki NAKAMORI, Takashi KIMURA, Tsuyoshi MATSUMURA, Harutoshi, FUJIMURA, Nobuyuki NUKINA, Hideki MOCHIZUKI, Saburo SAKODA, Minoru HORIE, Shouichi ICHIURA, Keiji IMOTO, Maurice SWANSON, Nicolas CHARLET BERGUERAND, Masanori TAKAHASHI.
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: San Sebastian, Spain
• [Presentation] The distribution of splicing defects in the Myotonic Dystrophy type 1 brain.
  • Author(s): Takashi KIMURA, Koichi SUENAGA, Masayuki NAKAMORI, Tsuyoshi MATSUMURA, Masanori TAKAHASHI, Harutoshi FUJIMURA, Kenji JINNAI, Hiroo YOSHIKAWA.
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: San Sebastian, Spain
• [Presentation] 筋強直性ジストロフィー症における中枢神経スプライシング異常の局在性の検討．
  • Author(s): 末永浩一、木村 卓、中森雅之、高橋正紀、松村剛、藤村晴俊、陣内研二、芳川浩男．
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京