Ultrastructural analysis of the membrane origin for autophagy

• Project/Area Number: 21790191
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: General anatomy (including Histology/Embryology)
• Research Institution: Juntendo University
• Principal Investigator: KOIKE Masato Juntendo University, 医学部, 准教授 (80347210)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: カテプシンD / ノックアウトマウス / 神経性セロイドリポフスチン蓄積症 / オートファゴソーム / LC3 / ユビキチン / p62 / Nbr1 / カテプシン / オートファジー / 隔離膜 / NBR1 / LC-3 / Atg9A / DFCP1

Research Abstract

Neurons in brains of cathepsin D-deficient (CD-/-) mice, a murine model for neuronal ceroid lipofuscinoses (NCLs), possess abundant autophagosomes and granular osmiophilic deposits (GRODs),which are often found in nascent autophagosomes. In addition to immunocytochemical localization of LC3 and ubiquitin in, p62 and Nbr1, both of which can interact with both ubiquitin and LC3, were found to be also localized on the membrane of GRODs. Moreover, these molecules were present in the same granules of the neurons. The data indicate that ubiquitin and p62 and/or Nbr1 on the membrane of GRODs may serve as a signal of autophagy that contributes to the pathogenesis of NCLs.

Research Products

• [Journal Article] Dissociation and dispersion of claudin-3 from the tight junction could be one of the most sensitive indicators of reflux esophagitis in a rat model of the disease. (2011)
  • Author(s): Oguro M, et al.
  • Journal Title: J Gastroenterol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Free fatty acids stimulate autophagy in pancreatic beta-cells via JNK pathway. (2010)
  • Author(s): Komiya, K., Uchida, T., Ueno, T., Koike, M., Abe, H., Hirose, T., Kawamori, R., Uchiyama, Y., Kominami, E., Fujitani, Y., Watada, H.
  • Journal Title: Biochem. Biophys. Res. Commun. 401(4) Pages: 561-567
  • Peer Reviewed
• [Journal Article] New neurons clear the path of astrocytic processes for their rapid migration in the adult brain. (2010)
  • Author(s): Kaneko, N., Marin, O., Koike, M., Hirota, Y., Uchiyama, Y., Murakami, F., Wu, J., Tessier-Levigne, M., Alvarez-Buylla, A., Okano, H., Rubenstein, J., Sawamoto, K.
  • Journal Title: Neuron 67(2) Pages: 213-223
  • Peer Reviewed
• [Journal Article] PAC1 gene knockout reveals an essential role of chaperone-mediated 20S proteasome biogenesis and latent 20S proteasomes in cellular homeostasis. (2010)
  • Author(s): Sasaki, K., Hamasaki, J., Koike, M., Hirano, Y., Komatsu, M., Uchiyama, Y., Tanaka, K., Murata, S.
  • Journal Title: Mol. Cell Biol. 30(15) Pages: 3864-3874
  • Peer Reviewed
• [Journal Article] Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking. (2010)
  • Author(s): Hadano, S., Otomo, A., Kunita, R., Suzuki-Utsunomiya, K., Akatsuka, A., Koike, M., Aoki, M., Uchiyama, Y., Itoyama, Y., Ikeda, J.E.
  • Journal Title: PLos One 5(3) Pages: 9805-9805
  • Peer Reviewed
• [Journal Article] Cathepsin L in bone marrow-derived cells is required for retinal and choroidal neovascularization. (2010)
  • Author(s): Shimada, N., Ohno-Matsui, K., Iseki, S., Koike, M., Uchiyama, Y., Peters, C., Wang, J., Yoshida, T., Mochizuki, M., Morita, I.
  • Journal Title: Am. J. Pathol. 176(5) Pages: 2571-2580
  • Peer Reviewed
• [Journal Article] LC3, a microtubule-associated protein1A/B light chain3, is involved in cytoplasmic lipid droplet formation. (2010)
  • Author(s): Shibata, M., Yoshimura, K., Tamura, H., Ueno, T., Nishimura, T., Inoue, T., Sasaki, M., Koike, M., Arai, H., Kominami, E., Uchiyama, Y.
  • Journal Title: Biochem. Biophys. Res. Commun. 393(2) Pages: 274-279
  • Peer Reviewed
• [Journal Article] Atg9A protein, an autophagy-related membrane protein, is localized in the neurons of mouse brains. (2010)
  • Author(s): Tamura, H., Shibata, M., Koike, M., Sasaki, M., Uchiyama, Y.
  • Journal Title: J. Histochem. Cytochem. 58(5) Pages: 443-453
  • Peer Reviewed
• [Journal Article] Ablation of C/EBPbeta alleviates ER stress and pancreatic beta cell failure through the GRP78 chaperone in mice. (2010)
  • Author(s): Matsuda, T., Kido, Y., Nakano-Hashimoto, N., Kaisho, T., Tanaka, T., Asahara, S., Shigeyama, Y., Takeda, A., Inoue, T., Shibutani, Y., Koyanagi, M., Hosooka, T., Matsumoto, M., Inoue, H., Uchida, T., Koike, M., Uchiyama, Y., Akira, S., Kasuga, M.
  • Journal Title: J. Clin. Invest. 120(1) Pages: 115-126
  • Peer Reviewed
• [Journal Article] PAC1 gene knockout reveals an essential role of chaperone-mediated 20S proteasome biogenesis and latent 20S proteasomes in cellular homeostasis. (2010)
  • Author(s): Sasaki K, et al.
  • Journal Title: Mol.Cell Biol. Volume: 30 Pages: 3864-3874
  • Peer Reviewed
• [Journal Article] New neurons clear the path of astrocytic processes for their rapid migration in the adult brain. (2010)
  • Author(s): Kaneko N, et al.
  • Journal Title: Neuron Volume: 67 Pages: 213-223
  • Peer Reviewed
• [Journal Article] Free fatty acids stimulate autophagy in pancreatic beta-cells via JNK pathway. (2010)
  • Author(s): Komiya K, et al.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 401 Pages: 561-567
  • Peer Reviewed
• [Journal Article] Atg9A protein, an autophagy-related membrane protein, is localized in the neurons of mouse brains. (2010)
  • Author(s): Tamura H, et al.
  • Journal Title: J Histochem Cytochem (in press)
  • Peer Reviewed
• [Journal Article] LC3, a microtubule-associated protein 1A/B light chain3, is involved in cytoplasmic lipid droplet formation. (2010)
  • Author(s): Shibata, M, et al.
  • Journal Title: Biophys Biochem Res Comm 393 Pages: 274-279
  • Peer Reviewed
• [Journal Article] Cathepsin L in bone marrow-derived cells is required for retinal and choroidal neovascularization. (2010)
  • Author(s): Shimada N, et al.
  • Journal Title: Am J Pathol (in press)
  • Peer Reviewed
• [Journal Article] Loss of ALS2/Alsin Exacerbates Motor Dysfunction in a SOD1^<H46R>-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking. (2010)
  • Author(s): Hadano S, et al.
  • Journal Title: PLoS ONE (in press)
  • Peer Reviewed
• [Journal Article] Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway. (2009)
  • Author(s): Maejima, Y., Sedbazar, U., Suyama, S., Kohno, D., Onaka, T., Takano, E., Yoshida, N., Koike, M., Uchiyama, Y., Fujiwara, K., Takahashi, N., Horvath, T.L., Dietrich, M.O., Tanaka, S., Dezaki, K., Oh-I, S., Hashimoto, K., Shimizu, H., Nakata, M., Mori, M., Yada, T.
  • Journal Title: Cell Metab. 10(5) Pages: 355-365
  • Peer Reviewed
• [Journal Article] オートファジーの超微形態観察 (2009)
  • Author(s): 小池正人、内山安男
  • Journal Title: 臨床検査 53(12) Pages: 1535-1541
• [Journal Article] 脳虚血とオートファジー,ユビキチン・プロテアソーム系の役割 (2009)
  • Author(s): 小池正人、内山安男
  • Journal Title: 医学のあゆみ 231(5) Pages: 347-351
• [Journal Article] Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. (2009)
  • Author(s): Sugita, S., Horie, S., Nakamura, O., Maruyama, K., Usui, Y., Takeuchi, M., Ishidoh, K., Koike, M., Uchiyama, Y., Peters, C., Yamamoto, Y., Mochizuki, M.
  • Journal Title: J. Immunol. 183(8) Pages: 5013-5022
  • Peer Reviewed
• [Journal Article] Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. (2009)
  • Author(s): Sugita S, et al.
  • Journal Title: J Immunol 183 Pages: 5013-5022
  • Peer Reviewed
• [Journal Article] Ablation of C/EBP beta alleviates ER stress and pancreatic beta cell failure through induction of GRP78. (2009)
  • Author(s): Matsuda, T, et al.
  • Journal Title: J Clin Invest 120 Pages: 115-126
  • Peer Reviewed
• [Journal Article] Nesfatin-1-regulated paraventricular oxytocinergic signaling causes anorexia through a leptin-independent melanocortin pathway. (2009)
  • Author(s): Maejima Y, et al.
  • Journal Title: Cell Metabolism 10 Pages: 355-365
  • Peer Reviewed
• [Journal Article] オートファジーの超微形態観察 (2009)
  • Author(s): 小池正人、内山安男
  • Journal Title: 臨床検査 225 Pages: 1535-1541
• [Journal Article] 脳虚血とオートファジー,ユビキチン・プロテアソーム系の役割 (2009)
  • Author(s): 小池正人、内山安男
  • Journal Title: 医学のあゆみ 231 Pages: 347-351
• [Journal Article] Dissociation and dispersion of claudin-3 from the tight junction could be one of the most sensitive indicators of reflux esophagitis in a rat model of the disease.
  • Author(s): Oguro, M., Koike, M., Ueno, T., Asaoka, D., Mori, H., Nagahara, A., Uchiyama, Y., Watanabe, S.
  • Journal Title: J Gastroenterol. in press.
  • NAID: 10029029126
• [Presentation] 海馬CA3錐体細胞特異的Atg7コンディショナルノックアウトマウスの形態学的解析 (2011)
  • Author(s): 小池正人、内山安男
  • Organizer: 第16回グリアクラブ
  • Place of Presentation: ヒルトンニセコビリッジ
  • Year and Date: 2011-02-02
• [Presentation] リソソームカテプシンD欠損とオートファジーについて (2011)
  • Author(s): 内山安男、小池正人
  • Organizer: 第1回放射線神経生物学研究集会
  • Place of Presentation: 群馬大学医学部刀城会館
  • Year and Date: 2011-01-29
• [Presentation] リソゾーム蓄積症の病態形成にオートファジーが果たす役割について (2011)
  • Author(s): 小池正人、内山安男
  • Organizer: 第6回オートファジー研究会
  • Place of Presentation: ヤマハリゾート「つま恋」
  • Year and Date: 2011-01-14
• [Presentation] ALS2, the causative gene product of familial motor neuron diseases, regulates autophagy-lysosomal protein degradation. (2010)
  • Author(s): Shinji Hadano, Asako Otomo, Ryota Kunita, Kyoko Suzuki-Utsunomiya, Akira Akatsuka, Masato Koike, Masaaki Aoki, Yasuo Uchiyama, Yasuoto Itoyama, Joh-E Ikeda.
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2010-12-07
• [Presentation] ALS2, the causative gene product of familial motor neuron diseases, regulates autophagy-lysosomal protein degradation. (2010)
  • Author(s): Shinji Hadano, ら
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2010-12-07
• [Presentation] 運動ニューロン疾患原因遺伝子産物ALS2の機能喪失はエンド・リソソーム系タンパク質分解異常をもたらす (2010)
  • Author(s): 秦野伸二、大友麻子、國田竜太、鈴木-宇都宮恭子、赤塚明、小池正人、青木正志、内山安男、糸山泰人、池田穰衛
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2010-09-03
• [Presentation] アストロサイトとの相互作用による新生ニューロン移動経路の形成・維持機構 (2010)
  • Author(s): 金子奈穂子、Oscar Marin、小池正人、廣田ゆき、内山安男、Jane Y Wu、 Qiang Lu : Marc Tessier-Lavigne、Arturo Alvarez-Buylla、岡野栄之、John L.R.Rubenstein、澤本和延
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2010-09-03
• [Presentation] オートファジー関連膜タンパク質であるAtg9Aはマウス脳の神経細胞に局在する (2010)
  • Author(s): 多村博澄、柴田昌宏、小池正人、佐々木光穂、内山安男
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2010-09-02
• [Presentation] リソゾームカテプシン群を欠損したマウスにおける軸索変性 (2010)
  • Author(s): 小池正人、内山安男
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2010-09-02
• [Presentation] Atg9A protein, an autophagy-related membrane protein, is localized in the neurons of mouse brains. (2010)
  • Author(s): Yasuo Uchiyama, Hirofumi Tamura, Masato Koike, Mitsuho Sasaki.
  • Organizer: 7th Forum of European Neuroscience
  • Place of Presentation: アムステルダム
  • Year and Date: 2010-07-06
• [Presentation] The role of macroautophagy in the pathogenesis of lysosomal storage disease due to cathepsin D deficiency. (2010)
  • Author(s): Masato Koike, Yasuo Uchiyama.
  • Organizer: 7th Forum of European Neuroscience
  • Place of Presentation: アムステルダム
  • Year and Date: 2010-07-05
• [Presentation] 低酸素-脳虚血負荷後の海馬錐体細胞におけるカスパーゼ非依存性神経細胞死の表情 (2010)
  • Author(s): 小池正人、内山安男
  • Organizer: 第115回日本解剖学会総会・全国学術集会
  • Place of Presentation: 岩手県民会館
  • Year and Date: 2010-03-29
• [Presentation] 哺乳類Atg9A mRNAノックダウン細胞株におけるリソソーム様構造物の生化学的解析 (2010)
  • Author(s): 佐々木光穂、多村博澄、小池正人、上野隆、内山安男
  • Organizer: 第115回日本解剖学会総会・全国学術集会
  • Place of Presentation: 岩手県民会館
  • Year and Date: 2010-03-28
• [Presentation] リソゾーム蓄積症の病態形成にオートファジーが果たす役割について (2010)
  • Author(s): 小池正人、柴田昌宏、内山安男
  • Organizer: 第15回グリアクラブ
  • Place of Presentation: ヒルトンニセコビリッジ
  • Year and Date: 2010-02-12
• [Presentation] 哺乳類Atg9A mRNAノックダウン細胞の形態学的解析 (2010)
  • Author(s): 多村博澄、佐々木光穂、小池正人、上野隆、内山安男
  • Organizer: 第115回日本解剖学会総会・全国学術集会
  • Place of Presentation: 岩手県民会館
• [Presentation] Resveratrol is beneficial to senescence-accelerated mouse neurons and to differentiated but not naive PC12 cells. (2009)
  • Author(s): Motoko Shiozai, Shoichi Takeuchi, Naoya Hayakawa, Masahiro Shibata, Masato Koike, Yasuo Uchiyama, Takahiro Gotow.
  • Organizer: 39th Annual Meeting Society for Neuroscience
  • Place of Presentation: シカゴ
  • Year and Date: 2009-10-21
• [Presentation] Axonal degeneration in mice doubly deficient in cathepsin D or B and L. (2009)
  • Author(s): Masato Koike, Yasuo Uchiyama.
  • Organizer: 39th Annual Meeting Society for Neuroscience
  • Place of Presentation: シカゴ
  • Year and Date: 2009-10-19
• [Presentation] Distribution of Atg9A, an autophagy-related membrane protein, Atg9, in mouse brains. (2009)
  • Author(s): Hirosumi Tamura, Masato Koike, Mitsuho Sasaki, Masahiro Shibata, Yasuo Uchiyama.
  • Organizer: 39th Annual Meeting Society for Neuroscience
  • Place of Presentation: シカゴ
  • Year and Date: 2009-10-19
• [Presentation] 神経細胞におけるリソソームプロテアーゼの役割に関する分子細胞生物学的研究 (2009)
  • Author(s): 小池正人
  • Organizer: 第50回日本組織細胞化学会総会・学術集会2009年度日本組織細胞化学会若手学術奨励賞受賞講演
  • Place of Presentation: ピアザ淡海 滋賀県立県民交流センター
  • Year and Date: 2009-09-27
• [Presentation] 神経細胞におけるリソソームプロテアーゼの役割に関する分子細胞生物学的研究 (2009)
  • Author(s): 小池正人
  • Organizer: 第50回日本組織細胞化学会総会・学術集会
  • Place of Presentation: ピアザ淡海(滋賀県)
  • Year and Date: 2009-09-27
• [Presentation] ヒトヘルペスウイルス6粒子のエクソソーム経路を利用した細胞外への放出機構について (2009)
  • Author(s): 小池正人、森康子、森石永子、河端暁子、湯華民、小柳津裕子、山西弘一、内山安男
  • Organizer: 第50回日本組織細胞化学会総会・学術集会
  • Place of Presentation: ピアザ淡海 滋賀県立県民交流センター
  • Year and Date: 2009-09-26
• [Presentation] Involvement of macroautophagy in the pathogenesis of lysosomal storage disease due to cathepsin D deficiency. (2009)
  • Author(s): Masato Koike, Masahiro Shibata, Masaaki Komatsu, Paul Saftig, Tetsuro Ishii, Eiki Kominami, Keiji Tanaka, Yasuo Uchiyama.
  • Organizer: 5th International Symposium on Autophagy
  • Place of Presentation: 大津プリンスホテル
  • Year and Date: 2009-09-26
• [Presentation] Involvement of macroautophagy in the pathogenesis of lysosomal storage disease due to cathepsin D deficiency. (2009)
  • Author(s): Masato Koike, ら、
  • Organizer: 5th International Symposium on Autophagy
  • Place of Presentation: 大津プリンスホテル(滋賀県)
  • Year and Date: 2009-09-26
• [Presentation] Distribution of Atg9A, an autophagy-related membrane protein, Atg9, in mouse brains. (2009)
  • Author(s): Hirosumi Tamura, ら
  • Organizer: 5th International Symposium on Autophagy
  • Place of Presentation: 大津プリンスホテル(滋賀県)
  • Year and Date: 2009-09-26
• [Presentation] ヒトヘルペスウイルス6粒子のエクソソーム経路を利用した細胞外への放出機構について (2009)
  • Author(s): 小池正人, ら
  • Organizer: 第50回日本組織細胞化学会総会・学術集会
  • Place of Presentation: ピアザ淡海(滋賀県)
  • Year and Date: 2009-09-26
• [Presentation] リソソーム蓄積症の病態形成にオートファジーが果たす役割について (2009)
  • Author(s): 小池正人、柴田昌宏、内山安男
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-09-18
• [Presentation] リソソーム蓄積症の病態形成にオートファジーが果たす役割について (2009)
  • Author(s): 小池正人、柴田昌宏、内山安男
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2009-09-18
• [Presentation] レスベラトロールの未分化及び分化PC12細胞における影響 (2009)
  • Author(s): 竹内翔一、塩崎元子、早川直哉、柴田昌宏、小池正人、内山安男、後藤隆洋
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-09-17
• [Presentation] エタノール障害中枢神経細胞に対するキサントシンの緩和作用 (2009)
  • Author(s): 早川直哉、塩崎元子、竹内翔一、柴田昌宏、小池正人、内山安男、後藤隆洋
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-09-17
• [Presentation] レスベラトロールはSAMP 10中枢神経系の老化関連変性を改善する (2009)
  • Author(s): 塩崎元子、竹内翔一、早川直哉、柴田昌宏、小池正人、内山安男、後藤隆洋
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-09-17
• [Presentation] レスベラトロールの未分化及び分化PC12細胞における影響 (2009)
  • Author(s): 竹内翔一, ら
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2009-09-17
• [Presentation] エタノール障害中枢神経細胞に対するキサントシンの緩和作用 (2009)
  • Author(s): 早川直哉, ら
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2009-09-17
• [Presentation] ルスベラトロールはSAMP10中枢神経系の老化関連変性を改善する (2009)
  • Author(s): 塩崎元子, ら
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2009-09-17
• [Presentation] Distribution of Atg9A, an autophagy-related membrane protein, Atg9, in mouse brains. (2009)
  • Author(s): Hirosumi Tamura, Masato Koike, Mitsuho Sasaki, Masahiro Shibata, Yasuo Uchiyama.
  • Organizer: 5th International Symposium on Autophagy
  • Place of Presentation: 大津プリンスホテル
• [Book] マウス低酸素-脳虚血負荷後の神経細胞死の遺伝学的検討(ブレインサイエンスレビュー2011)(伊藤正男・川合述史編集) (2011)
  • Author(s): 小池正人
  • Publisher: クバプロ
• [Book] ブレインサイエンスレビュー2011 (2011)
  • Author(s): 小池正人
  • Publisher: クバプロ
• [Remarks] ホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/shinkei_kozo/index.html
• [Patent(Industrial Property Rights)] オートファジー性細胞死抑制剤 (2011)
  • Inventor(s): 内山安男、砂堀毅彦、小池正人
  • Industrial Property Rights Holder: 内山安男、砂堀毅彦、小池正人
  • Industrial Property Number: 2011-054647
  • Filing Date: 2011-03-11