Evaluation of the role of new disease modifier variant chromogranin B in the common molecular pathology of neurodegenerative diseases

• Project/Area Number: 17K09756
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Okayama University
• Principal Investigator: Ohta Yasuyuki 岡山大学, 大学病院, 講師 (20746854)
• Co-Investigator(Kenkyū-buntansha): 阿部 康二 岡山大学, 医歯薬学総合研究科, 教授 (20212540) ; 山下 徹 岡山大学, 医歯薬学総合研究科, 講師 (60644408)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経変性疾患 / 疾患修飾遺伝子 / クロモグラニンB / 異常構造蛋白

Outline of Final Research Achievements

A novel neurodegenerative disease-modifying gene, chromogranin B (CHGB), is involved in motor neuron degeneration of amyotrophic lateral sclerosis (ALS) through intercellular transmission of misfolded proteins. Therefore, in order to clarify the role of CHGB on oxidative stress, which is a common pathology of several neurodegenerative diseases, we first established the method for analyzing oxidative stress over time in ALS mice. We created the double transgenic mouse by crossing ALS mouse (G93A-SOD1 mouse) and OKD mouse, which visualizes oxidative stress, and performed in vivo imaging and histological analysis. We clarified the involvement of oxidative stress in the degeneration of lower limb skeletal muscles and lumbar spinal motor neurons of ALS.

Academic Significance and Societal Importance of the Research Achievements

新規の神経変性疾患修飾遺伝子CHGBは、異常構造蛋白の細胞間伝播による神経変性を通じて、様々な神経変性疾患の共通病態である酸化ストレス増強に関わることが考えられている。本研究では、代表的神経変性疾患である筋萎縮性側索硬化症（ALS）のモデルマウスにおける、運動ニューロンおよび骨格筋変性への酸化ストレス関与を、in vivo imagingで経時的に観察する手法を確立した。本手法は様々な神経変性疾患モデルマウスに応用することが可能であり、今後はCHGBおよび他の因子についても酸化ストレスへの関与を経時的に解析することが可能である。

Research Products

• [Journal Article] Female dominant association of sarcopenia and physical frailty in mild cognitive impairment and Alzheimer's disease (2019)
  • Author(s): Ohta Y, Nomura E, Hatanaka N, Osakada Y, Matsumoto N, Sasaki R, Tsunoda K, Takemoto M, Tadokoro K, Hishikawa N, Wakutani Y, Yamashita T, Sato K, Omote Y, Abe K.
  • Journal Title: J Clin Neurosci. Volume: 70 Pages: 96-101
  • DOI: 10.1016/j.jocn.2019.08.062
  • Peer Reviewed
• [Journal Article] Imaging Hypoxic Stress and the Treatment of Amyotrophic Lateral Sclerosis with Dimethyloxalylglycine in a Mice Model (2019)
  • Author(s): Nomura Emi、Ohta Yasuyuki、Tadokoro Koh、Shang Jingwei、Feng Tian、Liu Xia、Shi Xiaowen、Matsumoto Namiko、Sasaki Ryo、Tsunoda Keiichiro、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Yamashita Toru、Kuchimaru Takahiro、Kizaka-Kondoh Shinae、Abe Koji
  • Journal Title: Neuroscience Volume: 415 Pages: 31-43
  • DOI: 10.1016/j.neuroscience.2019.06.025
  • Peer Reviewed
• [Journal Article] Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis. (2018)
  • Author(s): Ohta Y, Nomura E, Shang J, Feng T, Huang Y, Liu X, Shi X, Nakano Y, Hishikawa N, Sato K, Takemoto M, Yamashita T, Abe K.
  • Journal Title: J Neurosci Res. Volume: Epub ahead of print Issue: 5 Pages: 607-619
  • DOI: 10.1002/jnr.24368
  • NAID: 120006776453
  • Peer Reviewed
• [Journal Article] Affective improvement of neurological disease patients and caregivers using an automated telephone call service. (2018)
  • Author(s): Ohta Y, Yamashita T, Hishikawa N, Sato K, Hatanaka N, Takemoto M, Doutare S, Abe K.
  • Journal Title: J Clin Neurosci. Volume: 56 Pages: 74-78
  • DOI: 10.1016/j.jocn.2018.07.006
  • Peer Reviewed
• [Journal Article] Behavioral and affective features of amyotrophic lateral sclerosis patients. (2017)
  • Author(s): Ohta Y, Sato K, Takemoto M, Takahashi Y, Morihara R, Nakano Y, Tsunoda K, Nomura E, Hishikawa N, Yamashita T, Abe K
  • Journal Title: J Neurol Sci. Volume: 381 Pages: 119-125
  • DOI: 10.1016/j.jns.2017.08.024
  • Peer Reviewed
• [Journal Article] Familial amyotrophic lateral sclerosis of the G37V- superoxide dismutase 1 mutation with a slow disease progression. (2017)
  • Author(s): Tadokoro K, Ohta Y, Takahashi Y, Yamashita T, Sato K, Takemoto M, Hishikawa N, Abe K
  • Journal Title: Neurology and Clinical Neuroscience Volume: 5 Issue: 3 Pages: 96-98
  • DOI: 10.1111/ncn3.12123
  • Peer Reviewed
• [Journal Article] Potential multisystem degeneration in Asidan patients. (2017)
  • Author(s): Ohta Y, Yamashita T, Hishikawa N, Sato K, Matsuzono K, Tsunoda K, Hatanaka N, Takemoto M, Takemi T, Takamatsu K, Abe K
  • Journal Title: J Neurol Sci. Volume: 373 Pages: 216-222
  • DOI: 10.1016/j.jns.2017.01.003
  • Peer Reviewed
• [Journal Article] Detecting spinal pyramidal tract of amyotrophic lateral sclerosis patients with diffusion tensor tractography. (2017)
  • Author(s): Fukui Y, Hishikawa N, Sato K, Nakano Y, Morihara R, Shang J, Takemoto M, Ohta Y, Yamashita T, Abe K.
  • Journal Title: Neurosci Res. Volume: Epub ahead of print Pages: 58-63
  • DOI: 10.1016/j.neures.2017.11.005
  • Peer Reviewed
• [Journal Article] Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. (2017)
  • Author(s): Shang J, Yamashita T, Nakano Y, Morihara R, Li X, Feng T, Liu X, Huang Y, Fukui Y, Hishikawa N, Ohta Y, Abe K
  • Journal Title: Neuroscience. Volume: 350 Pages: 158-168
  • DOI: 10.1016/j.neuroscience.2017.03.024
  • Peer Reviewed
• [Presentation] Therapeutic benefits of edaravone for enhanced oxidative stress in mice model of amyotrophic lateral sclerosis (2019)
  • Author(s): Ohta Y, Nomura E, Shang J, Feng T, Liu X, Shi X, Hishikawa N, Takemoto M, Yamashita T, Abe K
  • Organizer: Brain 2019
  • Int'l Joint Research
• [Presentation] 新規遺伝性疾患 Asidan (SCA36)におけるDAT scanの特徴 (2019)
  • Author(s): 太田康之、山下徹、菱川望、佐藤恒太、角田慶一郎、幡中典子、武本麻美、商敬偉、阿部康二
  • Organizer: 第42回日本脳神経CI学会総会
• [Presentation] Therapeutic effects of edaravone for enhanced oxidative stress in amyotrophic lateral sclerosis mice (2019)
  • Author(s): Ohta Y, Nomura E, Shang J, Feng T, Nakano Y, Hishikawa N, Sato K, Takemoto M, Yamashita T, Omote Y, Abe K
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 新規酸化ストレスイメージングによるALSへのエダラボン治療効果の検討 (2019)
  • Author(s): 太田康之、野村恵美、山下徹、馮田、佐藤恒太、武本麻美、菱川望、表芳夫、阿部康二
  • Organizer: 第37回日本神経治療学会学術集会
• [Presentation] 筋萎縮性側索硬化症患者の前頭葉機能評価 (2019)
  • Author(s): 太田康之、山下徹、菱川望、佐藤恒太、武本麻美、表芳夫、阿部康二
  • Organizer: 第38回日本認知症学会学術集会
• [Presentation] Flow-metabolism uncoupling in the cervical spinal cord of ALS patients. (2018)
  • Author(s): Yamashita T, Nakano Y, Morihara R, Shang J, Sato K, Hishikawa N, Ohta Y, Abe K
  • Organizer: The 11th Pan Pacific Symposium on Stem Cells and Cancer Research
  • Int'l Joint Research
• [Presentation] The pathological role of P413L variant chromogranin B as disease modifier in female amyotrophic lateral sclerosis. (2018)
  • Author(s): Ohta Y, Soucy G, Phaneuf D, Audet JN, Gros-Louis F, Yamashita T, Sato K, Takemoto M, Hishikawa N, Julien JP, Abe K
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] ALSモデルマウス骨格筋における酸化ストレスの関与 (2018)
  • Author(s): 太田康之、野村恵美、商敬偉、山下徹、馮田、黄永、佐藤恒太、武本麻美、菱川望、阿部康二
  • Organizer: 日本筋学会第4回学術集会
• [Presentation] 筋萎縮性側索硬化症における前頭葉機能低下の特徴 (2018)
  • Author(s): 太田康之、山下徹、菱川望、佐藤恒太、武本麻美、幡中典子、高橋義秋、中野由美子、森原隆太、阿部康二
  • Organizer: 第8回日本認知症予防学会学術集会
• [Presentation] The role of variant chromogranin B as disease modifier in Japanese female amyotrophic lateral sclerosis. (2017)
  • Author(s): Ohta Y, Soucy G, Phaneuf D, Audet JN, Gros-Louis F, Yamashita T, Sato K, Takemoto M, Hishikawa N, Julien JP, Abe K
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 新しいSCA/ALS crossroad mutation AsidanのDWEP現象. (2017)
  • Author(s): 太田康之、山下徹、佐藤恒太、幡中典子、角田慶一郎、武本麻美、菱川望、阿部康二
  • Organizer: 第5回日本難病医療ネットワーク学会学術集会
• [Presentation] 虚血負荷によるTDP43、FUS/TLSの発現亢進と神経細胞保護効果の関係 (2017)
  • Author(s): 中野由美子、孫淼、山下徹、森原隆太、佐藤恒太、菱川望、太田康之、阿部康二
  • Organizer: 第17回日本抗加齢医学会総会
• [Presentation] アルツハイマー病におけるアセチルコリンエステラーゼ阻害剤変更の影響. (2017)
  • Author(s): 太田康之、菱川望、山下徹、佐藤恒太、武本麻美、阿部康二
  • Organizer: 第7回日本認知症予防学会学術集会
• [Presentation] Comparison of early stage clinical symptoms, cognitive, affective and ADL functions between PDD and DLB (2017)
  • Author(s): Takemoto T, Sato T, Hishikawa N, Yamashita T, Ohta Y, Hatanaka N, Abe K
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research