核酸代謝の乱れからみた蛋白質の老化基盤とその排除機構

2017 Fiscal Year Annual Research Report

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 26117006
• Research Institution: Niigata University
• Principal Investigator: 小野寺 理 新潟大学, 脳研究所, 教授 (20303167)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: RNA / ALS

Outline of Annual Research Achievements

認知症を引き起こすタンパク質は，生理的に存在するが，老化と共に“特定の神経システム“において“病原性をもったタンパク質へと変遷し蓄積”する．この課程には，“タンパク質の量的，質的な変化"を伴う．タンパク質の量は，産生と分解により制御され，産生はmRNA により，また分解は細胞内の分解機構と，細胞外への排出機構により制御される．質的な変化は，翻訳後修飾やpolyA結合部位の選択や，選択的スプライシングによるRNAの多様性により引き起こされる．老化では，この産生，分解，質が変遷し，病原性を持つタンパク質への引き金を引くと考え，これを検討する．特に神経システムの特性を決定する多様なRNAの制御機構に注目する．本研究は，神経疾患の病因タンパク質の老化を，その神経システム特異的なRNA制御機構の破綻の面から明らかとし，これを標的とした治療法の開発を目的とする．今までの成果で，加齢性神経変性疾患において，RNA代謝機構が乱れていることが示された．さらに，vivo モデルにてRNA代謝を乱すことで，TDP-43の断片化を引き起こし，かつアポトーシスを誘導することに成功した．得られた疾患モデルに対して，生化学的，免疫組織化学的な解析を加え,た. また，ヒトとマウスでは，この制御関連の塩基配列が異なるため，より理想的なモデルを作成するために，iPS由来のヒト神経細胞にて，同様の解析を加える．iPS に対し，内在性のRNA制御を乱し，RNA制御の乱れに対するヒト由来モデルを作成した．さらに，変性疾患の系統選択性は，その系統を獲得する発達過程での体細胞レベルのゲノム，エピゲノム情報の問題と考えると説明しやすい．具体的には，患者罹患組織での疾患関連遺伝子のエピゲノム情報の検討を行っている。またエピゲノム変化が、RNA代謝機構のゆらぎを引き起こすことを培養細胞系で、検討を加えた．

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

遺伝子改変を行わないRNA代謝のゆらぎを引き起こす疾患モデルを作成した

Strategy for Future Research Activity

最終年度は，このモデルの解析を更に進め．また恒久的な神経症状を引き起こす工夫を行う．またエピジェネティックな変化に関して，孤発性神経変性の背景にあるのか，さらに検討を加える．

Research Products

• [Int'l Joint Research] National Institute of Mental Health(India)
  • Country Name: India
  • Counterpart Institution: National Institute of Mental Health
• [Int'l Joint Research] Pennsylvania State University(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Pennsylvania State University
• [Journal Article] Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis (2018)
  • Author(s): Tohnai Genki、Nakamura Ryoichi、Sone Jun、Osamu Onodera et al.
  • Journal Title: Neurobiology of Aging Volume: 64 Pages: 158.e15～158.e19
  • DOI: 10.1016/j.neurobiolaging.2017.12.005
  • Peer Reviewed
• [Journal Article] Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data (2018)
  • Author(s): Sugai Akihiro、Kato Taisuke、Koyama Akihide、Koike Yuka、Kasahara Sou、Konno Takuya、Ishihara Tomohiko、Onodera Osamu
  • Journal Title: Frontiers in Neuroscience Volume: 12 Pages: epub
  • DOI: 10.3389/fnins.2018.00028
  • Peer Reviewed
• [Journal Article] CARASIL families from India with 3 novel null mutations in theHTRA1gene (2017)
  • Author(s): Preethish-Kumar Veeramani、Nozaki Hiroaki、Tiwari Sarbesh、Vengalil Seena、Bhat Maya、Prasad Chandrajit、Onodera Osamu、Uemura Masahiro、Doniparthi Seshagiri、Saini Jitender、Nashi Saraswati、Polavarapu Kiran、Nalini Atchayaram
  • Journal Title: Neurology Volume: 89 Pages: 2392～2394
  • DOI: 10.1212/WNL.0000000000004710
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review (2017)
  • Author(s): Ibrahimi Muhammad、Nozaki Hiroaki、Lee Angelica、Onodera Osamu、Reichwein Raymond、Wicklund Matthew、El-Ghanem Mohammad
  • Journal Title: Cerebrovascular Diseases Volume: 44 Pages: 135～140
  • DOI: 10.1159/000477358
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 遺伝性脳小血管病における微小出血の特徴 (2018)
  • Author(s): 上村昌寛, 野崎洋明, 酒井直子先生, 小野寺理
  • Organizer: 第43回日本脳卒中学会学術集会
• [Presentation] Promoting excellence in ALS registry and research. Hot topics: Molecular mechanism. ALS registry and research in Japan (2017)
  • Author(s): 小野寺理
  • Organizer: “PACTALS” and “Brain Protein Aging and Dementia Control” Project Joint Meeting
  • Int'l Joint Research / Invited
• [Presentation] How are neurovascular units maintained in aging? From a study of HSCVD (2017)
  • Author(s): 小野寺理
  • Organizer: Brain Protein Aging and Dementia Control, 2nd International Symposium
  • Int'l Joint Research / Invited
• [Presentation] 脳小血管病の分子病態：CARASILからのアプローチ (2017)
  • Author(s): 小野寺理
  • Organizer: 第36回日本認知症学会学術集会
  • Invited
• [Presentation] タンパク質老化に寄与する脳小血管ユニットの異常 －非神経細胞の視点から－ (2017)
  • Author(s): 小野寺理
  • Organizer: 新学術領域研究［グリアアセンブリ］［脳タンパク質老化］公開シンポジウム
  • Invited
• [Presentation] CARASIL：HTRA1活性の低下と脳小血管病 (2017)
  • Author(s): 小野寺理
  • Organizer: 第49回日本動脈硬化学会総会
  • Invited
• [Presentation] 脳小血管の機能と疾病の分子病態 (2017)
  • Author(s): 小野寺理
  • Organizer: 第8回日本脳血管・認知症学会総会
  • Invited
• [Presentation] The SMN2 gene copy number states can affect the onset risk and survival time in Japanese ALS (2017)
  • Author(s): Ishihara T, Toyoda S, Koyama A, Tada , Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS)
  • Organizer: 28th international symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] The alternative splicing of TARDBP mRNA is affected by the methylation status (2017)
  • Author(s): Yuka Koike, Akihiro Sugai, Akio Yokoseki, Osamu Onodera
  • Organizer: 28th international symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] A non-genetically modified iPSC-derived neuron model with an increased expression of intrinsic TDP-43 (2017)
  • Author(s): Akihiro Sugai, Genri Tohyama, Taisuke Kato, Tomohiko Ishihara, Osamu Onodera
  • Organizer: Amyotrophic lateral sclerosis & Related Motor Neuron Disease (Gordon Research Conference)
  • Int'l Joint Research
• [Presentation] The alternative splicing of TARDBP mRNA is affected by the ALS10 associated mutations and methylation status (2017)
  • Author(s): Yuka Koike, Akihiro Sugai, Takuya Konno, Akihide Koyama, Misaki Koyama, Taisuke Kato, Tomohiko Ishihara, Akio Yokoseki, Osamu Onodera
  • Organizer: Amyotrophic lateral sclerosis & Related Motor Neuron Disease (Gordon Research Conference)
  • Int'l Joint Research
• [Presentation] Molecular analysis of mutant high-temperature requirement serine protease A1 identified in patients with familial cerebral small vessel disease (2017)
  • Author(s): Uemura M, Nozaki H, Kato T, Koyama A, Onodera O
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] The absence of hypertension and the presence of psychiatric symptoms suggest a genetic disorder among patients suspected for hereditary cerebral small vessel disease (2017)
  • Author(s): Uemura M, Nozaki H, Sakai N, Onodera O
  • Organizer: The 8th Korea Joint Stroke Conference
  • Int'l Joint Research
• [Presentation] The prevalence estimates of HTRA1-associated cerebral small vessel disease (2017)
  • Author(s): Hiroaki Nozaki, Akihide Koyama, Masahiro Uemura, Taisuke Kato, Osamu Onodera
  • Organizer: The 8th Korea-Japan Joint Stroke Conference
  • Int'l Joint Research
• [Presentation] A NON-GENETICALLY MODIFIED HUMAN NEURONAL MODEL OF ALS WITH AN INCREASED EXPRESSION OF INTRINSIC TDP-43 (2017)
  • Author(s): A. Sugai, T. Kato, T. Ishihara, O. Osamu
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] The SMN2 gene copy number states can affect the onset risk and survival time in Japanese ALS (2017)
  • Author(s): Ishihara T, Toyoda S, Koyama A, Tada , Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS)
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Molecular analysis of mutant high-temperature requirement serine protease A1 identified in patients with familial cerebral small vessel disease (2017)
  • Author(s): Uemura M, Nozaki H, Kato T, Koyama A, Onodera O
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] “CORRECT” for introducing nucleotide substitution with CRISPR/Cas9 system in MAPT gene (2017)
  • Author(s): Yuka Koike, Akihide Koyama, Atsushi Shiga, Akio Yokoseki, Osamu Onodera
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] The prevalence estimates of HTRA1-associated cerebral small vessel disease (2017)
  • Author(s): Hiroaki Nozaki, Akihide Koyama, Masahiro Uemura, Taisuke Kato, Osamu Onodera
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] <Altered allele-specific gene expression by an ALS-causative TDP-43 mutation (2017)
  • Author(s): 須貝章弘、廣川祥子、小山哲秀、今野卓哉、小野寺理
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Serine protease HTRA1 deficiency induces arteriopathy in cerebral small vessels (2017)
  • Author(s): Kato T, Sekine Y, Fujita N, Nozaki H, Hirokawa S, Sato T, Onodera O
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] 家族性脳小血管病患者で報告された変異型HTRA1蛋白質の機能解析 (2017)
  • Author(s): 上村昌寛, 野崎洋明, 加藤泰介, 小山哲秀, 小野寺理
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Distinct mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL (2017)
  • Author(s): 野崎 洋明, 加藤 泰介, 水田 依久子, 水野 敏樹, 西澤 正豊,小野寺 理
  • Organizer: 第114回日本内科学会総会
• [Presentation] CARASIL症候性キャリアの一例 (2017)
  • Author(s): 野崎洋明, 伊藤 絢子, 阿部崇, 豊島靖子,佐藤晶, 橋立英樹, 五十嵐修一, 高橋均, 小野寺理, 柿田明美
  • Organizer: 第36回日本認知症学会学術集会
• [Presentation] Therapeutic strategy utilizing gene editing by CRISPR/Cas9 for polyglutamine disease using DRPLA model (2017)
  • Author(s): Kato T, Hirokawa S, Fujita N, Sato T, Tsuji S, Onodera O
  • Organizer: 第40回日本神経科学大会
• [Presentation] セリンプロテアーゼHTRA1の機能欠損は、脳小血管病を引き起こす; Serine protease HTRA1 deficiency induces arteriopathy in cerebral small vessels (2017)
  • Author(s): Kato T, Sekine Y, Fujita N, Nozaki H, Hirokawa S, Sato T, Onodera O
  • Organizer: 第40回日本神経科学大会
• [Presentation] Protease activity analysis of mutant high-temperature requirement serine protease A1 identified in patients with familial cerebral small vessel disease (2017)
  • Author(s): Uemura M, Nozaki H, Kato T, Koyama A, Onodera O
  • Organizer: 第40回日本神経科学大会
• [Presentation] “CORRECT” for introducing nucleotide substitution with CRISPR/Cas9 system in MAPT gene (2017)
  • Author(s): Yuka Koike, Akihide Koyama, Atsushi Shiga, Akio Yokoseki, Osamu Onodera
  • Organizer: 第40回日本神経科学大会．
• [Presentation] 家族性脳小血管病患者で同定された変異型HTRA1蛋白質のプロテアーゼ活性解析 (2017)
  • Author(s): 上村昌寛, 野崎洋明, 加藤泰介, 小山哲秀, 小野寺理
  • Organizer: 第47回新潟神経学夏季セミナー
• [Presentation] RVCL関連変異の細胞内局在についての検討． (2017)
  • Author(s): 笠原杏子, 加藤泰介, 野崎洋明, 小山哲秀, 小野寺理．
  • Organizer: 第36回日本認知症学会学術集会