Drug development improving mitochondrial pathology in Amyotrophic lateral sclerosis

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16K14574
• Research Institution: Tohoku University
• Principal Investigator: 福永 浩司 東北大学, 薬学研究科, 教授 (90136721)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: Sigma-1R / 筋萎縮側索硬化症 / 脳・神経

Outline of Annual Research Achievements

家族性筋萎縮側索硬化症 (ALS)は SOD1、TDP-43、FUS 等の遺伝子変異を伴い，運動神経が変性脱落する疾患である。ミトコンドリア障害が神経・筋変性の引き金となるが，家族性ALS の原因遺伝子変異がどのようにしてミトコンドリア障害を引き起こすのか不明である。28年度はSigma-1受容体（R）（E102Q）変異体がミトコンドリア障害を惹起するメカニズムを培養細胞系で明らかにした。Sigma-1R変異体はミトコンドリアATP産生を障害し，プロテオソーム活性を低下させることで神経細胞死を誘発した。29年度は脳組織からの抽出物したオルガネラを蔗糖密度勾配遠心法で分画して，脳内プロテオソーム活性測定系を確立した。脳組織におけるミトコンドリアコンプレックス活性を測定する実験系を確立した。さらに，ミトコンドリア障害に伴う酸化ストレスを脳組織で測定する系を確立した。現在，Sigma-1R 欠損マウスおよび Sigma-1R遺伝子改変マウスを作成中であり，脊髄運動神経および中枢神経でのミトコンドリア障害を解析する予定である。また、これまで培養細胞を用いて，Sigma-1R（E102Q）変異体ミトコンドリア障害はピルビン酸，アミノレブリン酸，Sigma-1Rアゴニストで修復できることを明らかにした。今後はALSのモデルであるSOD1 変異マウスとSigma-1R遺伝子改変マウスを掛け合わせることにより，若年発症で重篤な ALS モデル動物を作成する。重篤な ALS モデル動物において，ミトコンドリア障害の機序を解明し，ミトコンドリア治療薬（ピルビン酸、アミノレブリン酸、Sigma-1Rアゴニスト）の効果を動物モデルで検証する。

Research Products

• [Journal Article] Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling (2018)
  • Author(s): Husain N, Yabuki Y, Shinoda Y, Fukunaga K
  • Journal Title: Pharmacology Volume: 101 Pages: 309-321
  • DOI: 10.1159/000488083
  • Peer Reviewed
• [Journal Article] Reduced CaM kinase II and CaM Kinase IV activities underlie cognitive deficits in NCKX2 heterozygous mice (2018)
  • Author(s): Moriguchi S, Kita S, Yabuki Y, Inagaki R, Izumi H, Sasaki Y, Tagashira H, Horie K, Takeda J, Iwamoto T, Fukunaga K
  • Journal Title: Mol Neurobiol Volume: 55 Pages: 3889-3900
  • DOI: 10.1007/s12035-017-0596-1
  • Peer Reviewed
• [Journal Article] Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy (2018)
  • Author(s): Moriguchi S, Ishizuka T, Yabuki Y, Shioda N, Sasaki Y, Tagashira H, Yawo H, Yeh JZ, Sakagami H, Narahashi T, Fukunaga K
  • Journal Title: Mol Psychiatry Volume: 23 Pages: 211-221
  • DOI: 10.1038/mp.2016.187
  • Peer Reviewed
• [Journal Article] The T-type calcium channel enhancer SAK3 inhibits neuronal death following transient brain ischemia via nicotinic acetylcholine receptor stimulation (2017)
  • Author(s): Yabuki Y, Jing X, Fukunaga K
  • Journal Title: Neurochem. Int. Volume: 108 Pages: 272-281
  • DOI: 10.1016/j.neuint.2017.04.015
  • Peer Reviewed
• [Journal Article] Novel spiroimidazopyridine derivative SAK3 improves methimazole-induced cognitive deficits in mice (2017)
  • Author(s): Noreen H, Yabuki Y, Fukunaga K
  • Journal Title: Neurochem. Int. Volume: 108 Pages: 91-99
  • DOI: 10.1016/j.neuint.2017.03.001
  • Peer Reviewed
• [Journal Article] Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons. (2017)
  • Author(s): Shioda N, Yabuki Y, Wang Y, Uchigashima M, Hikida T, Sasaoka T, Mori H, Watanabe M, Sasahara M, Fukunaga K
  • Journal Title: Mol Psychiatry Volume: 22 Pages: 1205-1222
  • DOI: 10.1038/mp.2016.200
  • Peer Reviewed
• [Journal Article] Stimulation of the Sigma-1 Receptor and the Effects on Neurogenesis and Depressive Behaviors in Mice (2017)
  • Author(s): Fukunaga K and Moriguchi S
  • Journal Title: Adv Exp Med Biol Volume: 964 Pages: 201-211
  • DOI: 10.1007/978-3-319-50174-1_14
  • Peer Reviewed
• [Journal Article] Combined l-citrulline and glutathione administration prevents neuronal cell death following transient brain ischemia (2017)
  • Author(s): Matsuo K, Yabuki Y, Fukunaga K
  • Journal Title: Brain Res Volume: 1663 Pages: 123-131
  • DOI: 10.1016/j.brainres.2017.03.014
  • Peer Reviewed
• [Journal Article] Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer (2017)
  • Author(s): Yabuki Y, Matsuo K, Izumi H, Haga H, Yoshida T, Wakamori M, Kakei A, Sakimura K, Fukuda T, Fukunaga K
  • Journal Title: Neuropharmacology Volume: 117 Pages: 1-13
  • DOI: 10.1016/j.neuropharm.2017.01.011
  • Peer Reviewed
• [Journal Article] Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice (2017)
  • Author(s): Yabuki Y, Matsuo K, Hirano K, Shinoda Y, Moriguchi S, Fukunaga K
  • Journal Title: Pharmacology Volume: 99 Pages: 160-171
  • DOI: 10.1159/000452839
  • Peer Reviewed
• [Journal Article] Sigma-1受容体の生理機能と筋萎縮性側索硬化症との関連 (2017)
  • Author(s): 福永 浩司、篠田 康晴
  • Journal Title: 生化学 Volume: 89 Pages: 106-110
  • DOI: 10.14952/seikagaku.2017.890106
• [Presentation] Arachidonic acid treatment aggravates alpha-Synuclein aggregation in vitro and in situ (2018)
  • Author(s): ○Kohji Fukunaga, Yasushi Yabuki, Kazuya Matsuo, Yasuharu Shinoda
  • Organizer: AD/PD 2018
• [Presentation] Arachidonic acid treatment aggravates alpha-Synuclein aggregation in vitro and in situ (2018)
  • Author(s): ○Yasuharu Shinoda, An Cheng, Tetsunori Yamamoto, Yasushi Kawata, Kohji Fukunaga
  • Organizer: AD/PD 2018
• [Presentation] FABP3 deficiency impairs fear extinction memory (2017)
  • Author(s): ○Yasushi Yabuki, Ibuki Takahata, Kazuya Mastuo, Yuji Owada, Kohji Fukunaga
  • Organizer: Neuroscience 2017
• [Presentation] Mitochondrial dysfunction and oxidative stress in rat brain prenatally exposed to valproic acid (2017)
  • Author(s): ○Kazuya Matsuo, Yasushi Yabuki, and Kohji Fukunaga
  • Organizer: Neuroscience 2017
• [Presentation] Discovery of a novel intracellular dopamine D2 receptor function (2017)
  • Author(s): ○Kohji Fukunaga, Norifumi Shioda
  • Organizer: 第60回日本神経化学会大会