The role of BAG3/HSP70 complex in selective autophagic degradation of alpha-synuclein

• Project/Area Number: 24591272
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: WATANABE Yoshihisa 京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990)
• Co-Investigator(Kenkyū-buntansha): TANAKA Masaki 京都府立医科大学, 医学研究科, 准教授 (80264753) ; 徳田 隆彦 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80242692)
• Co-Investigator(Renkei-kenkyūsha): TOKUDA Takahiko 京都府立医科大学, 医学研究科, 教授 (80242692)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: α-シヌクレイン / オートファジー分解 / 凝集体形成 / p62 / オートファジー / リン酸化 / BAG3 / パーキンソン病

Outline of Final Research Achievements

The aim of this study is to elucidate the degradation and aggregate formation of α-synuclein associated with Parkinson's disease. α-Synuclein fibrils were introduced into cultured cells, and their degradation was examined immunocytochemically. Autophagy-associated proteins were colocalized to these aggregates. Their degradation was inhibited by knockdown of Atg-5. Moreover, the nucleation activity of α-synuclein fibrils was reduced by inhibition of the lysosomal protein cathepsin B, resulting in a decrease in α-synuclein aggregates. These results suggested that the cleavage of α-synuclein fibrils into lysosomes via autophagy and endocytosis was involved in α-synuclein-aggregate formation.

Research Products

• [Journal Article] Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils. (2015)
  • Author(s): Tsujimura A, Taguchi K, Watanabe Y, Tatebe H, Tokuda T, Mizuno T, Tanaka M.
  • Journal Title: Neurobiol Dis Volume: 73 Pages: 244-253
  • DOI: 10.1016/j.nbd.2014.10.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Different expression of alpha- synuclein in hippocampal neurons. (2014)
  • Author(s): Taguchi, K, Watanabe, Y, Tsujimura, A, Tatebe, H, Miyata, S, Tokuda, T, Mizuno, T, Tanaka, M
  • Journal Title: PLos One Volume: 9 Issue: 2 Pages: e89327-e89327
  • DOI: 10.1371/journal.pone.0089327
  • Peer Reviewed / Open Access
• [Journal Article] p62/SQSTM1-dependent autophagy of Lewy body-like α-synuclein inclusions (2012)
  • Author(s): Watanabe Y, Tatebe H, Taguchi K, Endo Y, Tokuda T, Mizuno T, Nakagawa M, Tanaka M
  • Journal Title: PLoS One Volume: 7 Issue: 12 Pages: e52868-e52868
  • DOI: 10.1371/journal.pone.0052868
  • Peer Reviewed
• [Presentation] Differential expression of alpha-synuclein with a cell-type dependent manner in vivo (2015)
  • Author(s): 田口勝敏、渡邊義久、辻村敦、田中雅樹
  • Organizer: 第120回日本解剖学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] パーキンソン病に見られるレビー小体凝集体の細胞内形成過程の解析 (2014)
  • Author(s): 辻村敦、田口勝敏、渡邊義久、田中雅樹
  • Organizer: 第４回４大学連携研究フォーラム
  • Place of Presentation: 京都
  • Year and Date: 2014-12-02
• [Presentation] Differential expression of alpha-synuclein in vitro and in vivo. (2014)
  • Author(s): Taguchi, K., Watanabe, Y., Tsujimura, A., Tanaka, M.
  • Organizer: 北米神経科学会2014
  • Place of Presentation: Washington, DC
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] 異常タンパク質凝集体におけるp62リン酸化. (2014)
  • Author(s): 渡邊義久
  • Organizer: 第8回オートファジー研究会
  • Place of Presentation: 札幌
  • Year and Date: 2014-11-10 – 2014-11-11
• [Presentation] レヴィ小体主要構成分子α-Synucleinの脳内発現解析. (2014)
  • Author(s): 田口勝敏、渡邊義久、辻村敦、田中雅樹
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] パーキンソン病関連分子α-Synucleinの多様な脳内発現プロファイルについて (2014)
  • Author(s): 田口勝敏、渡邊義久、辻村敦、田中雅樹
  • Organizer: 第119回日本解剖学会総会・全国学術集会
  • Place of Presentation: 下野市
• [Presentation] Differential expression of α-synuclein depends on cell-types in cultured neurons. (2013)
  • Author(s): Taguchi K, Watanabe Y, Tsujimura A, Tanaka M.
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都市
• [Presentation] α-Synuclein is present as a monomer in the biological fluid. (2013)
  • Author(s): Tatebe H, Tokuda T, Ishi Ryotaro, Watanabe Y, Taguchi K, Kasai T, Tsujimura A, Mizuta I, Mizuno T, Tanaka M, Nakagawa M.
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都市
• [Presentation] Transendocytosis is impaired in CADASIL mutant NOTCH3. (2013)
  • Author(s): Watanabe A, Watanabe Y, Tanaka M, Nakagawa M, Mizuno T.
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都市
• [Presentation] パーキンソン病関連蛋白質α-Synucleinの凝集体蓄積とマクロオートファジー (2013)
  • Author(s): 渡邊義久、田中雅樹
  • Organizer: 細胞内ロジスティクス・シンポジウム
  • Place of Presentation: 神戸市
• [Presentation] Autophagic clearance of Lewy body-like α-synuclein inclusions. (2013)
  • Author(s): Taguchi, K., Watanabe, Y., Tatebe, H., Endo, Y., Tokuda, T., Mizuno, T., Nakagawa, M., Tanaka, M.
  • Organizer: 11th International Conference On Alzheimer's & Parkinson's Diseases 2013
  • Place of Presentation: Florence, Italy
• [Presentation] p62/SQSTM1-dependent autophagy of Lewy body-like α-synuclein inclusions. (2012)
  • Author(s): Watanabe, Y., Tatebe, H., Taguchi, K., Endo, Y., Tokuda, T., Mizuno, T., Nakagawa, M., Tanaka, M.
  • Organizer: 14th International Congress of Histochemistry and Cytochemistry
  • Place of Presentation: Kyoto, Japan
• [Presentation] Differential expression patterns of α-synuclein in vivo and in vitro. (2012)
  • Author(s): Taguchi, K., Watanabe, Y., Tanaka, M.
  • Organizer: 14th International Congress of Histochemistry and Cytochemistry
  • Place of Presentation: Kyoto, Japan
• [Presentation] p62/SQSTM1-dependent autophagic clearance of Lewy body-like α-synuclein inclusions. (2012)
  • Author(s): Watanabe, Y., Tatebe, H., Taguchi, K., Endo, Y., Tokuda, T., Mizuno, T., Nakagawa, M., Tanaka, M.
  • Organizer: 42th annual meeting of the Society for Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] オートファジーによるα-synuclein凝集体と障害ミトコンドリアの分解 (2012)
  • Author(s): 渡邊義久、建部陽嗣、田口勝敏、遠藤泰久、徳田隆彦、水野敏樹、中川正法、田中雅樹
  • Organizer: 第35回日本神経科学会
  • Place of Presentation: 名古屋
• [Presentation] 家族性アルツハイマー病に共通するAb関連蛋白質の産生・代謝過程の検討 (2012)
  • Author(s): 大島洋一、徳田隆彦、田口勝敏、水田依子、渡邊義久、水野敏樹、冨山貴美、亀谷富由樹、森啓、田中雅樹、中川正法
  • Organizer: 第35回日本神経科学会
  • Place of Presentation: 名古屋
• [Presentation] 初代培養神経細胞を用いたα-シヌクレインの発現プロファイリング (2012)
  • Author(s): 田口勝敏、渡邊義久、田中雅樹
  • Organizer: 第35回日本神経科学会
  • Place of Presentation: 名古屋
• [Presentation] パーキンソン病治療薬開発を目的とした汽水域放線菌ライブラリーからのオートファジー誘導物質のスクリーニング
  • Author(s): 渡邊義久、辻村敦、田口勝敏、田中雅樹
  • Organizer: 4大学連携研究フォーラム
  • Place of Presentation: 京都市
• [Book] Nova Science Publishers Inc (2013)
  • Author(s): Watanabe, Y., Tsujimura, A., Taguchi, K., Tanaka, M.
  • Total Pages: 21
  • Publisher: α-Synuclein metabolism and aggregation in the pathogenesis of Parkinson’s disease. In: α-Synuclein: Functional Mechanisms, Structure and Role in Parkinson’s Disease.
• [Book] Physiological functions and pathology of neurosin/kallikrein 6 in the central nervous system. In: Chiba, I. and Kamio, T. editors. Serine Proteases: Mechanism, Structure and Evolution. (2012)
  • Author(s): Watanabe, Y. and Tanaka, M.
  • Total Pages: 9
  • Publisher: Nova Science Publishers Inc.