Exploring skeletal muscle pathology in spinal and bulbar muscular atrophy using in silico analysis.

• Project/Area Number: 22K15705
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nagoya University
• Principal Investigator: Iida Madoka 名古屋大学, 医学系研究科, 助教 (40815437)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2023: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 球脊髄性筋萎縮症 / 骨格筋病態 / In silico解析 / 治療薬開発 / in silico解析 / 細胞モデル / マウスモデル

Outline of Research at the Start

球脊髄性筋萎縮症（SBMA）は成人男性のみに発症する進行性の遺伝性神経筋疾患である。本研究課題では、in silico解析を活用してSBMAの骨格筋病態の解明を目指す。SBMA細胞モデルおよびマウスモデルを用いた既存の遺伝子発現解析の結果を利用して、骨格筋病態の改善が期待される候補薬をin silico解析により抽出し、SBMA細胞モデルやマウスモデルに投与して病態抑止効果を評価した上で、変化している分子シグナルに注目して骨格筋の分子病態を解明する。またパスウェイ解析ならびに薬剤データベースを用いて、候補薬の作用機序および他の組織への潜在的な効能について解析する。

Outline of Final Research Achievements

Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease. We aimed to elucidate the skeletal muscle pathophysiology of SBMA using gene expression analysis information available in the Gene Expression Omnibus (GEO) and the Library of Integrated Network-based Cellular Signatures (LINCS) databases. We identified drugs and their mechanisms of action that induce genetic alterations negatively correlated with the pathophysiology of SBMA. Among them, we selected eight drugs that are expected to ameliorate SBMA pathology. We administered them to a muscle cell model of SBMA and identified drugs that improved SBMA model cell viability and suppressed cell toxicity.
Some of the compounds are existing drugs and have potential for drug repositioning. The mechanism of action of one of the drugs targets the known pathophysiology of SBMA and we plan to confirm its effect in SBMA mouse models in the future.

Academic Significance and Societal Importance of the Research Achievements

球脊髄性筋萎縮症（SBMA）は成人男性のみに発症する進行性の遺伝性神経筋疾患である。約3割の患者は発症後20年で移動に車椅子が必要となり、呼吸筋の筋力低下により呼吸器感染症で死亡することが多い。現在リュープリン酢酸塩がSBMAの唯一の治療薬として日本で承認を受けているが、性ホルモン抑制や骨格筋の同化作用による副作用をみとめ、新規治療薬の開発が望まれている。本研究によりSBMAの病態理解が進み、新たな治療薬開発につながると考えられる。また治療薬開発のプロセスは他の疾患にも応用でき、SBMAのみならず多くの疾患の治療薬開発に結びつくことが期待される。

Research Products

• [Journal Article] Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy. (2024)
  • Author(s): Hirunagi T, Nakatsuji H, Sahashi K, Yamamoto M, Iida M, Tohnai G, Kondo N, Yamada S, Murakami A, Noda S, Adachi H, Sobue G, Katsuno M.
  • Journal Title: J Cachexia Sarcopenia Muscle Volume: 15 Issue: 1 Pages: 159-172
  • DOI: 10.1002/jcsm.13344
  • Peer Reviewed / Open Access
• [Journal Article] Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies. (2024)
  • Author(s): Fukami Y, Iijima M, Koike H, Yagi S, Furukawa S, Mouri N, Ouchida J, Murakami A, Iida M, Yokoi S, Hashizume A, Iguchi Y, Imagama S, Katsuno M.
  • Journal Title: Neurol Neuroimmunol Neuroinflamm. Volume: 11(2) Issue: 2
  • DOI: 10.1212/nxi.0000000000200199
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy (2023)
  • Author(s): Kataoka Mayumi、Sahashi Kentaro、Tsujikawa Koyo、Takeda Jun-ichi、Hirunagi Tomoki、Iida Madoka、Katsunoa Masahisa
  • Journal Title: Neuroscience Research Volume: - Pages: 58-65
  • DOI: 10.1016/j.neures.2023.04.007
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implication of denervation in sporadic inclusion body myositis (2022)
  • Author(s): Noda Seiya、Murakami Ayuka、Kazuta Tomoyuki、Hirano Satoko、Kimura Seigo、Nakanishi Hirotaka、Matsuo Koji、Tsujikawa Koyo、Yamada Shinichiro、Iida Madoka、Koike Haruki、Kuru Satoshi、Katsuno Masahisa
  • Journal Title: Journal of the Neurological Sciences Volume: 439 Pages: 120317-120317
  • DOI: 10.1016/j.jns.2022.120317
  • Peer Reviewed / Open Access
• [Journal Article] Label-free morphological sub-population cytometry for sensitive phenotypic screening of heterogenous neural disease model cells (2022)
  • Author(s): Imai Yuta、Iida Madoka、Kanie Kei、Katsuno Masahisa、Kato Ryuji
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 9296-9296
  • DOI: 10.1038/s41598-022-12250-0
  • Peer Reviewed / Open Access
• [Journal Article] Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy (2022)
  • Author(s): Ogura Yosuke、Sahashi Kentaro、Hirunagi Tomoki、Iida Madoka、Miyata Takaki、Katsuno Masahisa
  • Journal Title: Cell Death & Disease Volume: 13 Issue: 7 Pages: 601-601
  • DOI: 10.1038/s41419-022-05001-6
  • Peer Reviewed / Open Access
• [Journal Article] Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis. (2022)
  • Author(s): Murakami, A., Noda, S., Kazuta, T., Hirano, S., Kimura, S., Nakanishi, H., Matsuo, K., Tsujikawa, K., Iida, M., Koike, H., Sakamoto, K., Hara, Y., Kuru, S., Kadomatsu, K., Shimamura, T., Ogi, T., Katsuno, M.
  • Journal Title: Ann Clin Transl Neurol. Volume: 9 Issue: 10 Pages: 1602-1615
  • DOI: 10.1002/acn3.51657
  • Peer Reviewed / Open Access
• [Presentation] Single cell analysis reveals oligodendrocyte heterogeneity in spinal and bulbar muscular atrophy (2023)
  • Author(s): 飯田 円
  • Organizer: 第64回日本神経学会学術大会
• [Book] CLINICAL NEUROSCIENCE (2022)
  • Author(s): 飯田 円
  • Total Pages: 3
  • Publisher: 中外医学社