Development of a new treatment for CNS demyelinating disorders targeting glucose and monocarboxylate transporter

• Project/Area Number: 17K16124
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Kyushu University
• Principal Investigator: Watanabe Mitsuru 九州大学, 病院, 助教 (30748009)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 多発性硬化症 / 視神経脊髄炎関連疾患 / Balo病 / グルコース担体 / アストロサイト / ミクログリア / GFAP / ニューロフィラメント / 視神経脊髄炎 / グリア細胞 / 乳酸担体 / 軸索障害 / バイオマーカー / 中枢神経脱髄疾患 / 脱髄疾患

Outline of Final Research Achievements

In Balo's concentric demyelinating lesion, GLUT5 and TMEM119 (marker of resident microglia) positive microglia were preferentially seen in most outer layer (acute active demyelinating lesion). Therefore, this finding suggests that GLUT5 is expressed on resident microglia and involved in active lesion formation.
Experimental autoimmune encephalomyelitis in oligodendrocyte-specific connexin 47 knockout mouse showed severer course than in control. In neuromyelitis optica spectrum disorders (NMOSD), serum glial fibrillary acidic protein and neurofilament light chain (NfL) levels were higher than in healthy controls. The decrease of serum NfL levels per month after relapse was significantly smaller in NMOSD than in multiple sclerosis. Taken together, in NMOSD, astrocytic damage may disturb trophic support from astrocyte to neuron and cause sustained neuronal damage even in the remission phase. These findings showed the importance of neuron-glial syncytium in demyelinating disorders.

Academic Significance and Societal Importance of the Research Achievements

中枢神経脱髄疾患において、コネキシン蛋白やグルコース担体、乳酸担体などの発現が変化していることから、神経細胞やグリア同士の機能的連絡障害（グリアシンシチウムの破綻）が病態に関与していることを提唱し、今回コネキシンの障害により多発性硬化症モデルが悪化すること、アストロサイト障害により軸索障害が遷延する可能性を示した。中枢神経系脱髄性疾患を理解するうえで、免疫細胞や一つの中枢神経系の細胞のみに注目するのでは不十分であり、様々な細胞が相互につながりをもっていることを踏まえて病態を評価することが重要である。

Research Products

• [Presentation] 血清GFAPとニューロフィラメント軽鎖は視神経脊髄炎関連疾患や多発性硬化症の障害度や再発率と相関する (2018)
  • Author(s): 渡邉 充ら
  • Organizer: 第30回日本神経免疫学会学術集会
• [Presentation] Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in neuromyelitis optica spectrum disorders (2018)
  • Author(s): Watanabe M, et al.
  • Organizer: ECTRIMS 2018
  • Int'l Joint Research
• [Presentation] Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as potential biomarkers for disease activity and disability in neuromyelitis optica spectrum disorders and multiple sclerosis (2018)
  • Author(s): Watanabe M, et al.
  • Organizer: PACTRIMS 2018
  • Int'l Joint Research