Lysosomal PolyQ accumulation as a target for treatment of SCA6

• Project/Area Number: 25282241
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Watase Kei 東京医科歯科大学, 学内共同利用施設等, 准教授 (30376800)
• Co-Investigator(Kenkyū-buntansha): 水澤 英洋 国立研究開発法人国立精神・神経医療研究センター, 病院, 病院長 (30144091)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2013: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 脊髄小脳変性症6型 / プルキンエ細胞 / 神経炎症 / リソソーム / カルシウムチャンネル / ミクログリア / ポリグルタミン / 脊髄小脳変性症 / 神経変性 / ノックインマウス

Outline of Final Research Achievements

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease characterized by a slowly progressive loss of cerebellar Purkinje cell and motor impairments. In SCA6, a protein containing an expanded polyglutamine stretch gradually accumulates in the cerebellar Purkinje cells but the molecular mechanisms leading to neurodegeneration remains largely elusive. In this study, we have shown that neuroinflammation is involved in the pathogenesis of SCA6. More importantly, by modulating the activation of microglial cells in the cerebellum of a faithful mouse model of SCA6, we succeeded in ameliorating their neurodegenerative phenotypes in the early disease phase.

Research Products

• [Journal Article] RpA1 ameliorates symptoms of mutant Ataxin-1 knock-in mice and enhances DNA damage repair (2016)
  • Author(s): Taniguchi, JB., Kondo, K., Fujita, K., Chen, X., Homma, H., Sudo, T., Mao, Y., Watase, K., Tanaka, T., Tagawa, K., Tamura, T., Muramatsu, SI., Okazawa, H.
  • Journal Title: Human Molecular Genetics Volume: 25 Pages: 4432-4447
  • DOI: 10.1093/hmg/ddw272
  • Peer Reviewed
• [Journal Article] Impaired striatal dopamine release in homozygous Vps35 D620N knock-in mice. (2016)
  • Author(s): Hebisawa, A., Aizawa, H., Cui, W., Fujita, Y., Hashimoto, K., Ajioka, I., Mizusawa, H., Yokota, T. and Watase K.
  • Journal Title: Human Molecular Genetics Volume: 25 Pages: 4507-4517
  • Peer Reviewed
• [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] Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1. (2015)
  • Author(s): Hatanaka Y., Watase K., Wada K., Nagai Y.
  • Journal Title: Sci. Rep. Volume: 5 Issue: 1 Pages: 16102-16102
  • DOI: 10.1038/srep16102
  • Peer Reviewed / Open Access
• [Journal Article] Spinocerebellar ataxia type 6: Lessons from faithful knock-in mouse models.n mouse models. (2015)
  • Author(s): Kei Watase
  • Journal Title: Neurology and Clinical Neuroscience Volume: 3 Issue: 1 Pages: 14-17
  • DOI: 10.1111/ncn3.137
  • Peer Reviewed
• [Presentation] SCA6病態におけるミクログリア炎症性応答 (2016)
  • Author(s): 渡瀬啓
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県神戸市）
  • Year and Date: 2016-05-20
  • Invited
• [Presentation] SCA6病態におけるミクログリア炎症性応答 (2016)
  • Author(s): 渡瀬 啓
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-20
  • Invited
• [Presentation] M1-dominant microglial response precedes Purkinje cell loss in the cerebellum of SCA6-knockin mouse models. (2015)
  • Author(s): Watase K, Aikawa, T., Mogushi, K., Iijima-Tsutui, K., Ishikawa, K., Sakurai, M., Tanaka H., Mizusawa, H.
  • Organizer: 25th Biennial Meeting, International Society for Neurochemistry
  • Place of Presentation: Cairns, QLD, Australia
  • Year and Date: 2015-08-26
  • Int'l Joint Research
• [Presentation] Early neuroinflammatory response precedes Purkinje cell loss in the cerebellum of SCA6-knockin mouse models. (2015)
  • Author(s): Kei Watase
  • Organizer: Gordon Research Conference: CAG Triplet Repeat Disorders
  • Place of Presentation: Lucca (Barga) Italy
  • Year and Date: 2015-05-31 – 2015-06-05
• [Presentation] Early neuroinflammatory response precedes Purkinje cell loss in the cerebellum of SCA6-knockin mouse models. (2015)
  • Author(s): Watase K, Aikawa, T., Mogushi, K., Iijima-Tsutui, K., Ishikawa, K., Sakurai, M., Tanaka H., Mizusawa, H.
  • Organizer: Gordon Research Conference
  • Place of Presentation: Barga, Italy
  • Year and Date: 2015-05-31
  • Int'l Joint Research
• [Presentation] Early neuroinflammatory response in SCA6 mouse models. (2014)
  • Author(s): Aikawa, T., Mogushi, T., Iijima, K., Tanaka, H., Mizusawa, H. and Watase, K.
  • Organizer: 第５５回日本神経学会学術大会
  • Place of Presentation: 福岡
• [Book] ブレインサイエンスレビュー２０１５ (2015)
  • Author(s): 渡瀬 啓
  • Total Pages: 256
  • Publisher: クバプロ