The relationship between spinocerebellar ataxia type 6 and microglial neuroinflammation

• Project/Area Number: 26860661
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Aikawa Tomonori 東京医科歯科大学, 脳統合機能研究センター, 助教 (10597149)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脊髄小脳失調症６型 / Cav2.1 / ポリグルタミン病 / プルキンエ細胞変性 / ミクログリア / Toll like receptor / MyD88 / neuroinflammation / SCA6 / TLR

Outline of Final Research Achievements

Spinocerebellar ataxia type 6 (SCA6) is dominantly inherited neurodegenerative disease, caused by CAG repeat expansion in the Cav2.1 calcium channel. Its key pathological features include selective cerebellar Purkinje cell (PC) loss. However, its molecular basis remains elusive. Here, we studied the cerebellar gene expression patterns of young Sca6-MPI118Q/118Q knockin mice, which recapitulated many phenotypic features of human SCA6. Temporal expression profiles of the candidate genes revealed that the up-regulation of microglial related genes was initiated before PC loss and was augmented as the disease progressed. Histological analysis of the MPI118Q/118Q cerebellum showed the activation of microglia and elevation of Toll-like receptor (TLR) 2, 7 expressions. Genetic ablation of MyD88, TLR-adaptor protein, ameliorated PC loss and partially rescued motor impairments. These results suggest that early neuroinflammatory response may play an important role in the pathogenesis of SCA6.

Research Products

• [Journal Article] Loss of MyD88 alters neuroinflammatory response and attenuates early Purkinje cell loss in a spinocerebellar ataxia type 6 mouse model (2015)
  • Author(s): Aikawa T, Mogushi K, Iijima-Tsutsui K, Ishikawa K, Sakurai H, Tanaka H, Mizusawa H, Watase K
  • Journal Title: Human molecular genetics Volume: 24（17） Issue: 17 Pages: 4780-4791
  • DOI: 10.1093/hmg/ddv202
  • Peer Reviewed / Open Access
• [Journal Article] Loss of MyD88 alters neuroinflammatory response and attenuates early Purkinje cell loss in a spinocerebellar ataxia type 6 mouse model. (2015)
  • Author(s): Tomonori Aikawa, Kaoru Mogushi, Kumiko Iijima, Kinya Ishikawa, Miyano Sakurai, Hiroshi Tanaka, Hidehiro Mizusawa and Kei Watase
  • Journal Title: Human Molecular Genetics Volume: -
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Genetical studies on knockin mice carrying a PARK17 mutation. (2015)
  • Author(s): Nobutaka Ishizu, Akira Hebisawa, Daishi Yui, Tomonori Aikawa, Hidehiro Mizusawa, Takanori Yokota, Kei Watase.
  • Organizer: 55th annual meeting of the Japanese Society of Neurology 2015
  • Place of Presentation: 朱鷺メッセ（新潟）
  • Year and Date: 2015-05-22
• [Presentation] 脊髄小脳失調症６型モデルマウスの早期炎症反応は病変形成に関与する (2015)
  • Author(s): 相川知徳, 茂櫛 薫, 飯島 久美子, 櫻井 美弥乃, 石川 欽也, 田中 博, 水澤 英洋, 渡瀬 啓
  • Organizer: 第７回CBIR+ONSA共催若手インスパイアシンポジウム(口演)
  • Place of Presentation: 東京医科歯科大学
  • Year and Date: 2015-02-21
• [Presentation] 脊髄小脳失調症６型マウスモデルにおける早期神経炎症 (2014)
  • Author(s): 相川知徳, 茂櫛 薫, 飯島 久美子, 櫻井 美弥乃, 田中 博, 水澤 英洋, 渡瀬 啓
  • Organizer: 第55回日本神経学会学術大会 (口演：脊髄小脳変性症：遺伝 ほか)
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-05-21 – 2014-05-24
• [Remarks] 脊髄小脳失調症6型の進行に脳内免疫システムが関与～神経変性疾患の治療開発につながることを期待～
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20150618.pdf
• [Remarks] 脊髄小脳失調症６型の進行に脳内免疫システムが関与 ～神経変性疾患の治療開発につながることを期待～
  • URL: http://www.jst.go.jp/pr/announce/20150618/