CSF-1受容体異常によるミクログリア機能破綻と一次性ミクログリア病の病態

• Project Area: Glial assembly: a new regulatory machinery of brain function and disorders
• Project/Area Number: 16H01331
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Niigata University
• Principal Investigator: 池内 健 新潟大学, 脳研究所, 教授 (20372469)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2016: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: ミクログリア / 大脳白質 / 認知症 / シグナル伝達 / 神経変性

Outline of Annual Research Achievements

ミクログリアは発生・分化から成熟期に至るまで脳の恒常性の維持に重要な役割を果たしている。そのようなミクログリアの機能に着目し、本課題ではミクログリアの機能異常が大脳白質変性の原因となる「一次性ミクログリア病」について研究を実施した。一次性ミクログリア病の代表例として、colony sitimulating factor 1（CSF1受容体）変異を原因とする神経軸索スフェロイド形成を伴うびまん性白質脳症（hereditary diffuse leukoencephalopathy with spheroids: HDLS）を研究対象として解析した。HDLS患者に同定される既報における遺伝子変異は，CSF1受容体のtyrosine kinaseドメインに集中している。本研究により，HDLS患者に新規変異を同定した。新規変異の中には，細胞外領域に存在するp.His362Arg，膜近傍領域に存在するp.Glu573Lys，キナーゼ挿入領域に存在するp.Gly747Argが含まれる。p.His362Argとp.Gly747Argはリガンド依存性のCSF1受容体の自己リン酸化が保たれており，病原性を示さないbenign polymorphismsと思われた。p.Glu573Lysは，CSF1受容体の自己リン酸化の部分喪失が生じていた。HDLS患者剖検脳から界面活性剤を用いてタンパクを抽出し，CSF1受容体及びミクログリア関連マーカー（DAP12, CD11b）のタンパク発現が低下していることを明らかにした。これらの結果から，CSF1受容体異常を起点としたミクログリア異常がHDLSの分子病態に関与していることが示唆された。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Mayo Clinic Jacksonville/Mayo Clinic Rochester(米国)
• [Journal Article] Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) (2018)
  • Author(s): Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda S, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T
  • Journal Title: European Journal of Neurology Volume: 25 Issue: 1 Pages: 142-147
  • DOI: 10.1111/ene.13464
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Partial loss of function of CSF1R in a patient with white matter abnormalities. (2018)
  • Author(s): Konno T, Miura T, Harriott A, Mezaki N, Edwards ES, Ross OA, Meschia JF, Ikeuchi T, Wszolek ZK
  • Journal Title: European Journal of Neurology Volume: 印刷中 Issue: 6 Pages: 875-881
  • DOI: 10.1111/ene.13611
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation (2017)
  • Author(s): Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda S, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T
  • Journal Title: European Journal of Neurology Volume: 24 Issue: 1 Pages: 37-45
  • DOI: 10.1111/ene.13125
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Diagnostic value of brain calcifications in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (2017)
  • Author(s): Konno T, Broderick DF, Mezaki N, Isami A, Kaneda D, Tashiro Y, Tokutake T, Keegan M, Woodruff BK, Miura T, Nozaki H, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T
  • Journal Title: American Journal of Neuroradiology Volume: 38 Issue: 1 Pages: 77-83
  • DOI: 10.3174/ajnr.a4938
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids (2016)
  • Author(s): Tada M，Konno T，Tada M, Tezuka T, Okazaki K, Arakawa M，Itoh K，Yamamoto T, Yokoo H, Yoshikura N，Ishihara K, Horie M, Takebayashi H, Toyoshima Y, Naito M, Onodera O, Nishizawa M, Takahashi H, Ikeuchi T，Kakita A
  • Journal Title: Annals of Neurology Volume: 80 Issue: 4 Pages: 554-565
  • DOI: 10.1002/ana.24754
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Partial loss of autophosphorylation of CSF1R in a patient with familial ischemic cerebrovascular syndrome (2017)
  • Author(s): Konno T, Harriott, Miura T, Mezaki N, Ross OA, Edwards ES, Meschia JF, Ikeuchi T, Wszolek ZK
  • Organizer: Annual Meeting of American Neurological Association
  • Int'l Joint Research
• [Presentation] Identification and functional assay of novel missense mutations of CSF1R in patients with HDLS/ALSP (2017)
  • Author(s): Miura T, Mezaki N, Ishiguro T, Tokutake T, Kasuga K, Konno T, Nozaki H, Onodera O, Ikeuchi T
  • Organizer: World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 分子遺伝学を基盤とした成人発症大脳白質脳症の理解 (2017)
  • Author(s): 池内 健
  • Organizer: 第36回日本認知症学会
  • Invited
• [Presentation] Proposed diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmeneted glia (2016)
  • Author(s): Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda S, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T
  • Organizer: 68th Annual Meeting of American Academy of Neurology
  • Place of Presentation: Vancouver, Canada
  • Int'l Joint Research
• [Presentation] White matter calcifications in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (2016)
  • Author(s): Konno T, Wszolek Z, Broderick D, Ikeuchi T, Onodera O
  • Organizer: Keystone Symposia Conference
  • Place of Presentation: Keystone, Colorado, USA
  • Int'l Joint Research
• [Presentation] Clinical characterization of Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. (2016)
  • Author(s): Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda S, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T
  • Organizer: 141st Annual Meeting of American Neurological Association
  • Place of Presentation: Baltimore, MD, USA
  • Int'l Joint Research