The polarized localization of p62 and NBR1 in cathepsin D-deficient neurons is involved in selective autophagy

• Project/Area Number: 25670099
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Juntendo University
• Principal Investigator: UCHIYAMA Yasuo 順天堂大学, 医学部, 教授 (10049091)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: オートファゴソーム / p62 / NBR1 / リソソーム / ニューロン

Outline of Final Research Achievements

The present study revealed that p62/NBR1, adapter proteins of selective autophagy, localize in somatodendrites of neurons in cathepsin D (CD)-deficient mouse brains but not in axons. This localization pattern of p62 and NBR1 was confirmed in primary cultured cortical neurons, while the N-terminal specific domains of these proteins were responsible for the polarized localization. We further examined the intraneuronal target components of p62 and NBR1 and found that the target organelle was dysfunctional lysosomes in CD-deficient neurons. These results suggest that the polarized localization of p62 and NBR1 contributes to the selective autophagy in the somatodendrites of neurons.

Research Products

• [Journal Article] Property of Lysosomal Storage Disease associated with Midbrain Pathology in the CNS of LAMP-2-deficient Mice. (2015)
  • Author(s): Furuta A, Kikuchi H, Fujita H, Yamada D, Fujiwara Y, Kabuta T, Nishino I, Wada K, Uchiyama Y
  • Journal Title: Am J Pathol Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study (2015)
  • Author(s): Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N
  • Journal Title: Lancet Neurol Volume: 14 Pages: 274-282
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Long-Term Safety Issues of iPSC-Based Cell Therapy in a Spinal Cord Injury Model: Oncogenic Transformation with Epithelial-Mesenchymal Transition. (2015)
  • Author(s): Nori S, Okada Y, Nishimura S, Ssaki T, Itakura G, Kobayashi Y, Renault-Mihara F, Shimizu A, Koya I, Yoshida R, Kudoh J, Koike M, Uchiyama Y, Ikeda E, Toyama Y, Nakamura M, Okano H
  • Journal Title: Stem Cell Rep Volume: 4 Pages: 1-14
  • Peer Reviewed / Open Access
• [Journal Article] Axonal accumulation of alpha-synuclein in Gaucher disease model of medaka (Oryzias latipes) does not contribute to neurodegeneration. (2015)
  • Author(s): Uemura N, Koike M, Ansai K, Kinoshita M, Fujiwara-Ishikawa T, Matsui H, Naruse K, Sakamoto N, Uchiyama Y, Todo T, Takeda S, Yamakado H, Takahashi R
  • Journal Title: Pros Genetics Volume: 11
  • Peer Reviewed / Open Access
• [Journal Article] Cellular localization and tissue distribution of endogenous DFCP1 protein. (2015)
  • Author(s): Nanao T, Koike M, Yamaguchi J, Sasaki M, Uchiyama Y
  • Journal Title: Biomed Res Volume: 36 Pages: 121-133
  • NAID: 130005065279
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Super-Ecliptic, pHluorin-mKate2, Tandem Fluorescent Protein-Tagged Human LC3 for the Monitoring of Mammalian Autophagy. (2015)
  • Author(s): Tanida I, Ueno T, Uchiyama Y
  • Journal Title: Pros ONE Volume: 9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased immunoreactivity of cathepsins in the rat esophagus under chronic acid reflux esophagitis. (2014)
  • Author(s): Suyama M, Koik M, Asaoka D, Mori H, Oguro M, Ueno T, Nagahara A, Watanabe S, Uchiyama U
  • Journal Title: J Histochem Cytochem Volume: 62 Pages: 645-660
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spatotemporal expression of TRPM4 in the mouse cochlea. (2014)
  • Author(s): Sakuraba M, Murata J, Teruyama R, Kamiya K, Yamaguchi J, Okano Y, Uchiyama Y, Ikeda K
  • Journal Title: J Neurosci Res Volume: 92 Pages: 1409-1418
  • Peer Reviewed / Open Access
• [Journal Article] Nirtic oxide-mediated injury of interstitial cells of Cajal and intestinal dysmotility under endotoxemia. (2014)
  • Author(s): Ueshima S, Nishida T, Koike M, Matsuda H, Sawa Y, Uchiyama Y
  • Journal Title: Biomed Res Volume: 35 Pages: 251-262
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pancreatic β cell failure mediated by mTORC1 hyperactivity and autophagic Pancreatic β cell failure mediated by mTORC1 hyperactivity and autophagic impairment. (2014)
  • Author(s): Bartolome A, Kimura-Koyanagi M, Asahara S, Guillén C, Teruyama K, Inoue H, Shimizu S, Kanno A, García-Aguilar A, Koike M, Uchiyama Y, Benito M, Noda T, Kido Y
  • Journal Title: Diabetes Volume: 63 Pages: 2996-3008
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of the selective secretion 5-HT receptor antagonist ramosetron on duodenal acidification-induced gastric hypersensitivity in rats. (2014)
  • Author(s): Nakafuku-Fukuda M, Hirata T, Keto Y, Yamano M, Yokoyama T, Uchiyama Y
  • Journal Title: Eur J Pharmacol Volume: 731 Pages: 88-92
  • Peer Reviewed / Open Access
• [Journal Article] NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization. (2014)
  • Author(s): Yamanaka T, Tosaki A, Kurosawa M, Matsumoto G, Koike M, Uchiyama Y, Maity SN, Shimogori T, Hattori N, Nukina N
  • Journal Title: Nat Commun Volume: 5 Pages: 3354-3354
  • Peer Reviewed / Open Access
• [Journal Article] SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. (2014)
  • Author(s): Yokono M, Takasu T, Hayashizaki Y, Mitsuoka K, Kihara R, Muramatsu Y, Miyoshi S, Tahara A, Kurosaki E, Li Q, Tomiyama H, Sasamata M, Shibasaki M, Uchiyama Y
  • Journal Title: Eur J Pharmacol Volume: 727 Pages: 66-74
  • Peer Reviewed / Open Access
• [Journal Article] Deregulation of Pancreas-Specific Oxidoreductin ERO1β in the Pathogenesis of Diabetes Mellitus. (2014)
  • Author(s): Awazawa M, Futami T, Sakada M, Kaneko K, Ohsugi M, Nakaya K, Terai A, Suzuki R, Koike M, Uchiyama Y, Kadowaki T, Ueki K
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 1290-1299
  • Peer Reviewed / Open Access
• [Journal Article] Immunocytochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in normal and steatotic human livers. (2014)
  • Author(s): Kashima J, Shintani-Ishida K, Nakajima M, Maeda H, Unuma K, Uchiyama Y, Yoshida K
  • Journal Title: Hepatol Res Volume: 44 Pages: 779-787
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of the selective secretion 5-HT receptor antagonist ramosetron on duodenal acidification-induced gastric hypersensitivity in rats. (2014)
  • Author(s): Nakafuku-Fukuda, M., Hirata, T., Keto, Y., Yamano, M., Yokoyama, T., Uchiyama, Y.
  • Journal Title: Eur J Pharmacol Volume: -
  • Peer Reviewed
• [Journal Article] NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization. (2014)
  • Author(s): Yamanaka, T., Tosaki, A., Kurosawa, M., Matsumoto, G., Koike, M., Uchiyama, Y., Maity, S.N., Shimogori, T., Hattori, N., *Nukina, N.
  • Journal Title: Nat Commun Volume: -
  • Peer Reviewed
• [Journal Article] Deregulation of Pancreas-Specific Oxidoreductin ERO1β in the Pathogenesis of Diabetes Mellitus. (2014)
  • Author(s): Awazawa, M., Futami, T., Sakada, M., Kaneko, K., Ohsugi, M., Nakaya, K., Terai, A., Suzuki, R., Koike, M., Uchiyama, Y., Kadowaki, T., Ueki, K.
  • Journal Title: Mol Cell Biol Volume: -
  • Peer Reviewed
• [Journal Article] Generation and analysis of serine protease inhibitor Kazal type 3-Cre driver mice. (2014)
  • Author(s): Sakata, K., Ohmuraya, M., Araki, K., Suzuki C, Ida S, Hashimoto D, Wang J, Uchiyama Y, Baba H, *Yamamura K
  • Journal Title: Exp Animals Volume: 63 Pages: 45-53
  • NAID: 130003391605
  • Peer Reviewed
• [Journal Article] Local apoptosis modulates early mammalian brain development through the elimination of morphogen-producing cells. (2013)
  • Author(s): Nonomura, K., Yamaguchi, Y., Hamachi, M., Koike, M., Uchiyama, Y., Nakazato, K., Mochizuki, A., Sakaue-Sawano, A., Miyawaki, A., Yoshida, H., Kuida, K., *Miura, M.
  • Journal Title: Dev Cell Volume: 27 Pages: 621-634
  • Peer Reviewed
• [Journal Article] Exendin-4 improves beta cell function in autophagy-deficient beta cells. (2013)
  • Author(s): Abe, H., Uchida, T., Hara, A., Mizukami, H., Komiya, K., Koike, M., Shigihara, N., Toyofuku, Y., Ogihara, T., Uchiyama, Y., Yagihashi, S., Fujitani, Y., Watada, H.
  • Journal Title: Endicrinology Volume: 154 Pages: 4512-4524
  • Peer Reviewed
• [Journal Article] Immunocytochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in normal and steatotic human livers. (2013)
  • Author(s): Kashima, J., Shintani-Ishida, K., Nakajima, M., Maeda, H., Unuma, K., Uchiyama, Y., *Yoshida, K.
  • Journal Title: Hepatology Research Volume: -
  • Peer Reviewed
• [Journal Article] Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway. (2013)
  • Author(s): Okura, H., Kobayashi, T., Koike, M., Ohsawa, M., Zhang, D., Arai, H., Uchiyama, Y., *Hino O
  • Journal Title: Int J Oncol Volume: 43 Issue: 2 Pages: 447-456
  • DOI: 10.3892/ijo.2013.1984
  • Peer Reviewed
• [Journal Article] Particle size of latex beads dictates IL-1 production mechanism. (2013)
  • Author(s): Adachi, T., Takahara, K., Taneo, J., Uchiyama, Y., *Inaba, K.
  • Journal Title: PLos One Volume: 8
  • Peer Reviewed
• [Journal Article] Enrichment of GABARAP relative to LC3 in the axonal initial segments of neurons. (2013)
  • Author(s): Koike, M., Tanida, I., Nanao, N., Tada, N., Iwata, J., Ueno, T., Kominami, E., *Uchiyama, Y.
  • Journal Title: PLos One Volume: 8
  • Peer Reviewed
• [Journal Article] ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons. (2013)
  • Author(s): Matsui, H., #Sato, F., Sato, S., Koike, M., Taruno, Y., Saiki, S., Funayama, M., Ito, H., Taniguchi, Y., Uemura, N., Toyoda, A., Sakaki, Y., Takeda, S., Uchiyama, Y., Hattori, N., *Takahashi, R.
  • Journal Title: FEBS letters Volume: 9 Pages: 1316-25
  • Peer Reviewed
• [Journal Article] Biogenesis and proteolytic processing of lysosomal DNase II. (2013)
  • Author(s): Ohkouchi S, Shibata M, Sasaki M, Koike M, Safig P, Peters C, Nagata S, *Uchiyama Y
  • Journal Title: PLos One Volume: 8
  • Peer Reviewed
• [Journal Article] Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease. (2013)
  • Author(s): Furuta, A., Wakabayashi, K., Haratake, J., Kikuchi, H., Kabuta, T., Mori, F., Tokonami, F., Katsumi, Y., Tanioka, F., Uchiyama, Y., Nishino, I., Wada, K.
  • Journal Title: Acta Neuropathol Volume: 125 Pages: 459-461
  • Peer Reviewed
• [Journal Article] Differences in expression patterns of cathepsin C/dipeptidyl peptidase I in normal, pathological and aged mouse central nervous systems. (2013)
  • Author(s): Koike, M., Shibata, M., Ezaki, J., Peters, C., Saftig, P., Kominami, E., Uchiyama, Y.
  • Journal Title: Eur J Neurosci Volume: 37 Pages: 816-830
  • Peer Reviewed
• [Presentation] 神経系におけるオートファジー (2014)
  • Author(s): 内山安男
  • Organizer: 第５５回に本組織細胞化学会総会
  • Place of Presentation: 松本
  • Year and Date: 2014-09-27
  • Invited
• [Presentation] オートファジーと認知症 (2014)
  • Author(s): 内山安男
  • Organizer: 第２０回近畿老年期認知症研究会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-05
  • Invited
• [Presentation] リソソーム蓄積症とオートファジー (学術教育講演) (2014)
  • Author(s): 内山 安男
  • Organizer: 第１１９回日本解剖学会総会•全国学術集会
  • Place of Presentation: 自治医科大学
  • Invited
• [Presentation] 神経細胞の極性とオートファジー (2014)
  • Author(s): 内山 安男
  • Organizer: 第１９回グリアクラブ特別講演
  • Place of Presentation: 新潟
  • Invited
• [Presentation] 神経系におけるオートファジー (2014)
  • Author(s): 内山 安男
  • Organizer: 大阪大学蛋白質研究所セミナー 「オートファジーと疾患」
  • Place of Presentation: 大阪大学蛋白質研究所
  • Invited
• [Presentation] Memorial lecture for the Late Prof. emer. Tsuneo Fujita – Lesson from “Science” of Prof. Fujita. (2013)
  • Author(s): Yasuo Uchiyama
  • Organizer: The 23rd International Symposium on Morphological Sciences
  • Place of Presentation: Niigata
  • Invited
• [Presentation] 電子顕微鏡方法論.
  • Author(s): 内山 安男
  • Organizer: （独）医薬基盤研セミナー
  • Place of Presentation: （独）医薬基盤研究所
  • Invited
• [Book] Autophagy regulates lipid droplet formation and adipogenesis. In: Lipid metabolism. Ed by Rodrigo Valenzuela Baez. (2013)
  • Author(s): Uchiyama Y, Kominami E
  • Publisher: InTech