Molecular mechanisms of autophagic neuron death

2008 Fiscal Year Final Research Report

• Project/Area Number: 16GS0315
• Research Category: Grant-in-Aid for Creative Scientific Research
• Allocation Type: Single-year Grants
• Research Institution: Juntendo University (2008); Osaka University (2004-2007)
• Principal Investigator: UCHIYAMA Yasuo Juntendo University, 医学部, 教授 (10049091)
• Co-Investigator(Kenkyū-buntansha): WAGURI Satoshi 福島県立医科大学, 医学部, 教授 (30244908) ; SHIBATA Masahiro 新潟大学, 医歯学系, 准教授 (10343253) ; KOIKE Masato 順天堂大学, 医学部, 准教授 (80347210)
• Project Period (FY): 2004 – 2008
• Keywords: オートファジー / 神経細胞 / リソソーム / カテプシン / 脳虚血

Research Abstract

Hypoxia/ischemia (H/I) brain injury at birth is an important cause of cerebral palsy, mental retardation, and epilepsy. The H/I insult also causes energy failure, oxidative stress, and unbalanced ion fluxes, leading to high induction of autopahgy in brain neurons. Induction of neuronal autophagy after H/I injury is generally considered neuroprotective, as it maintains cellular homeostasis. However, our recent results show that cell death of hippocampal pyramidal neurons following neonatal H/I injury is largely prevented by Atg7 deficiency. This is the first report that we are aware of providing direct evidence for autophagy-induced neuron death after neonatal mouse H/I brain injury, using mice that cannot execute autophagy specifically in CNS tissue. Thus, therapeutic strategies to inhibit autophagy-induced neuron death may prove beneficial in the treatment of both pediatric and adult H/I brain injury.

Research Products

• [Journal Article] LC3, a microtubule-associated proteinlA/B light chain3, is involved in cytoplasmic lipid droplet formation. (2010)
  • Author(s): Shibata Yoshimura K, Tamura H, Ueno T, Nishimura T, Inoue T, Sasaki M, Koike M, Arai H, Kominami E, Uchiyama Y
  • Journal Title: BBRC 393 Pages: 274-279
• [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 Pages: 443-453
• [Journal Article] Chondrogenesis during the ES cell differentiation in vitro. (2010)
  • Author(s): Yagita Y, HorieK, Yamanaka I, Koinuma S, Shigeyoshi Y, Kawakami K, Takeda J, Uchiyama Y
  • Journal Title: PNAS 107 Pages: 3846-3851
• [Journal Article] The MAP1-LC3 conjugation system is involved in lipid droplet formation. (2009)
  • Author(s): Shibata M*, Yoshimura K*, Furuya M, Koike M, Ueno T, Komatsu M, Arai H, Tanaka K, Kominami E, Uchiyama Y
  • Journal Title: BBRC 382 Pages: 419-423
• [Journal Article] The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. (2009)
  • Author(s): Nada S*, Hondo A*, Kasai A*, Koike M*, Saito K, Uchiyama Y, Okada M
  • Journal Title: EMBO J 28 Pages: 477-489
• [Journal Article] Participation of autophagy in the initiation of graft dysfunction after rat liver transplantation. (2009)
  • Author(s): Gotoh K, Lu Z, Morita M, Shibata M, Koike M, Waguri S, Dono K, Doki Y, Kominami E, Sugioka A, Monden M, Uchiyama Y
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• [Journal Article] Autophagy-Physiology and Pathophysiology. (2008)
  • Author(s): Uchiyama Shibata M, Koike M, Yoshimura K, Sasaki M
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• [Journal Article] Autophagic neuron death in neonatal brain ischemia/hypoxia. (2008)
  • Author(s): Uchiyama Y, Koike M, Shibata M
  • Journal Title: Autophagy 4 Pages: 404-408
• [Journal Article] Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. (2008)
  • Author(s): Koike M, Shibata S, Tadakoshi T, Gotoh K, Komatsu M, Waguri S, KawaharaN, Kuida K, Nagata S, Kominami E, Tanaka K, Uchiyama Y
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• [Journal Article] Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. (2008)
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  • Journal Title: Mol Brain 1 Pages: 17
• [Journal Article] The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. (2008)
  • Author(s): Sou YS, Waguri S, Iwata JI, Ueno T, Fujimura T, Hara T, Sawada N, Yamada A, Mizushima N, Uchiyama Y, Kominami E, Tanaka K, Komatsu M
  • Journal Title: Mol Biol Cell 19 Pages: 4762-4775
• [Journal Article] GPHR is a novel anion channel critical for acidification and functions of the Golgi apparatus. (2008)
  • Author(s): Maeda Y, Ide T, Koike M, Uchiyama Y, Kinoshita T
  • Journal Title: Nat Cell Biol 10 Pages: 1135-1145
• [Journal Article] Human herpesvirus-6 induces MVB formation and virus egress occurs via an exosomal release pathway. (2008)
  • Author(s): Mori Y*, Koike M*, Moriishi E, Kawabata A, Tang H, Oyaizu H, Uchiyama Y, Yamanishi K
  • Journal Title: Traffic 9 Pages: 1728-1742
• [Journal Article] Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy. (2008)
  • Author(s): Oppenheim RW, Blomgren K, Ethell DW, Koike M, Komatsu M, Prevette D, Roth KA, Uchiyama Y, Vinsant S, Zhu C
  • Journal Title: J Neurosci 28 Pages: 1490-1497
• [Journal Article] Participation of autophagy in renal ischemia/reperfusion injury. (2008)
  • Author(s): Suzuki C, Takabatake Y, Tanaka H, Koike M, Shibata M, Uchiyama Y, Takahara S, Imai E, Isaka Y
  • Journal Title: BBRC 368 Pages: 100-106
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. (2008)
  • Author(s): Klionsky DJ, et al(alphabeticalに220番目)
  • Journal Title: Autophagy 4 Pages: 151-175
• [Journal Article] Specific depletion of GGA2 causes cathepsin D missorting in HeLa cells. (2007)
  • Author(s): Hida T, Ikeda H, Kametaka S, Akazawa S, Kohsaka S, Ebisu S, Uchiyama Y, Waguri S
  • Journal Title: Arch Histol Cytol 70 Pages: 303-312
• [Journal Article] Identification of Tim-4 as a phosphatidylserine receptor. (2007)
  • Author(s): Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S
  • Journal Title: Nature 450 Pages: 435-439
• [Journal Article] Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. (2007)
  • Author(s): Komatsu M, Waguri S, Koike M, Soul Y, Ueno T, Hara H, Mizushima N, Iwata J, Ezaki J, MurataS, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka T
  • Journal Title: Cell 131 Pages: 1149-1163
• [Journal Article] Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice. (2007)
  • Author(s): Yamasaki R, Zhang J, Koshiishi I, Suniarti DFS, Wu Z, Peters C, Schwake M, Uchiyama Y, Kira J, Saftig P, Utsumi H, Nakanishi H
  • Journal Title: Mol Cell Neurosci 35 Pages: 573-584
• [Journal Article] Degradation of nuclear DNA by DNase II-like acid DNase in cortical fiber cells of mouse eye lens. (2007)
  • Author(s): Nakahara M, Nagasaka A, Koike M, Uchida K, Kawane K, Uchiyama Y, Nagata S
  • Journal Title: FEBS J 274 Pages: 3055-3064
• [Journal Article] Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons. (2007)
  • Author(s): Komatsu M, Ueno T, Waguri S, Uchiyama Y, Kominami E, Tanaka K
  • Journal Title: ell Death Diff 14 Pages: 887-894
• [Journal Article] Cathepsin D Deficiency Induces Persistent Neurodegeneration in the Absence of Bax-Dependent Apoptosis. (2007)
  • Author(s): Shacka JJ, Klocke BJ, Young C, Shibata M, Olney JW, Uchiyama Y, Saftig P, Roth KA
  • Journal Title: J Neurosci 27 Pages: 2081-2090
• [Journal Article] Kainic acid induces early and transient autophagic stress in mouse hippocampus. (2007)
  • Author(s): Shacka JJ, Lu J, Xie ZL, Uchiyama Y, Roth KA, Zhang J
  • Journal Title: Neurosci Lett 414 Pages: 57-60
• [Journal Article] Reguration of autophagy by extracellular signal regulated protein kinases during 1-methyl-4-phenylpyridinium injury. (2006)
  • Author(s): Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT
  • Journal Title: Am J Pathol 170 Pages: 75-86
• [Journal Article] The luminal domain participates in the endosomal trafficking of the cation-independent mannose 6-phosphate receptor. (2006)
  • Author(s): Waguri S, Tomiyama Y, Hida T, Sakai N, Taniike M, Wakasugi M, Ebisu S, Uchiyama Y
  • Journal Title: Exp. Cell Res 312 Pages: 4090-4107
• [Journal Article] Effects of RNA interference of Atg4B on the limited proteolysis of LC3 in PC12 cells and expression of Atg4B in various rat tissues. (2006)
  • Author(s): Yoshimura K, Shibata M, Koike M, Gotoh K, Fukaya M, Watanabe M, Uchiyama Y
  • Journal Title: Autophagy 2 Pages: 200-208
• [Journal Article] Loss of autophagy in the central nervous system causes neurodegeneration. (2006)
  • Author(s): Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Ueno T, Koike M, Uchiyama Y, Kominami E' Tanaka K
  • Journal Title: Nature 441 Pages: 880-884
• [Journal Article] Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. (2006)
  • Author(s): Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K, Hagberg H
  • Journal Title: J Neurochem 96 Pages: 1016-1027
• [Journal Article] Bafilomycin A1 Inhibits Chloroquine-Induced Death of Cerebellar Granule Neurons. (2006)
  • Author(s): Shacka JJ, Klocke BJ, Shibata M, Uchiyama Y, Datta G, Schmidt RE, Roth KA
  • Journal Title: Mol Pharacol 69 Pages: 1125-1136
• [Journal Article] Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). (2005)
  • Author(s): Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E, Gotow G, Peters C, Figura Kv, Mizushima N, Saftig P, Uchiyama Y
  • Journal Title: Am J Pathol 167 Pages: 1713-1728
• [Journal Article] Macroautophagy-a novel amyloid-b (Ab) peptide-generating athway activated in alzheimer's disease. (2005)
  • Author(s): Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, J Naslund, Mathews PM, Cataldo AM, Nixon RA
  • Journal Title: J Cell Biol 171 Pages: 87-98
• [Journal Article] Phosphatidylserine妖ependent engulfment by macrophages of nuclei from erythroid precursor cells. (2005)
  • Author(s): Yoshida H, Kawane K, Koike M, Mori Y, Uchiyama Y, Nagata, S
  • Journal Title: Nature 434 Pages: 754-758
• [Journal Article] Proteolytic Degradation of Glutamate Decarboxylase Mediates Disinhibition of Hippocampal CA3 Pyramidal Cells in Cathepsin D-deficient Mice. (2005)
  • Author(s): Shimizu T, Hayashi Y, Yamada J, Zhang J, Yamasaki J, Ukai K, Koike M, Mine K, Figura Kv, Peters C, Saftig P, Fukuda T, Uchiyama Y, Nakanishi H
  • Journal Title: J Neurochem 94 Pages: 680-690
• [Journal Article] Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. (2005)
  • Author(s): Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T
  • Journal Title: J Cell Biol 169 Pages: 425-434
• [Journal Article] Participation of autophagy in the degeneration process of rat hepatocytes after transplantation following prolonged cold preservation. (2005)
  • Author(s): CDLuZ, DonoK, GotohK, Shibata M, Koike M, Marubashi S, Miyamoto A, Takeda Y, Nagano H, Umeshita K, Uchiyama Y, Monden M
  • Journal Title: Arch Histol Cytol 68 Pages: 71-80
• [Journal Article] The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. (2005)
  • Author(s): Zhu C, Wang X, Xu F, Bahr BA, Shibata M, Uchiyama Y, Hagberg H, Blomgren K
  • Journal Title: Cell Death Differ 12 Pages: 162-176
• [Journal Article] Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. (2004)
  • Author(s): Yu WH, Kumar A, Peterhoff C, Shapiro Kulnane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA
  • Journal Title: Int J Biochem Cell Biol 36 Pages: 2531-2540
• [Journal Article] Early-phase redistribution of the cation-independent mannose 6-phosphate receptor by U18666A treatment in HeLa cells. (2004)
  • Author(s): Wl'omiyama Y, Waguri S, Kanamori S, Kametaka S, Wakasugi M, Shibata M, Ebisu S, Uchiyama Y
  • Journal Title: Cell Tissue Res 317 Pages: 253-264
• [Journal Article] Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice. (2004)
  • Author(s): 0HanayamaR, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S
  • Journal Title: Science 304 Pages: 1147-1150
• [Presentation] Involvement of autophagy in pathogenesis of neuronal ceroid lipofuscinosis (2009)
  • Author(s): Uchiyama Y
  • Organizer: 12th International Congress on Neuronal Ceroid Lipofuscinoses (NCL) in Hamburg
  • Place of Presentation: Germany
  • Year and Date: 20090603-20090606
• [Presentation] Impairment and acceleration of autophagy: neurodegeneration (2008)
  • Author(s): Uchiyama Y
  • Organizer: In the 20th International Symposium on Morphological Science in Timisoara
  • Place of Presentation: Plenary Lecture
  • Year and Date: 20080912-20080917
• [Presentation] p62/A170/SQSTM1, a binding partner of ubiquitin and LC3, and lysosomal storage disorder (2008)
  • Author(s): Uchiyama Y
  • Organizer: Neuroscience 2008 in the 31st Annual Meeting
  • Place of Presentation: Tokyo
  • Year and Date: 20080709-20080711
• [Presentation] Impairment and acceleration of autophagy result in neurodegeneration. (2008)
  • Author(s): Uchiyama Y
  • Organizer: The 5th Asia Pacific International Congress of Anatomists
  • Place of Presentation: Tehran
  • Year and Date: 20080516-20080619
• [Presentation] オートラァジー/リソソーム制裁防正万秀子細胞生物学的研究 (2008)
  • Author(s): 内山安男
  • Organizer: 平成2 0年度顕微鏡学会瀬藤賞受賞講演
  • Place of Presentation: 千葉大学
  • Year and Date: 2008-10-17
• [Presentation] In: Neuronal macroautophagy, autophagic stress, and neurological diseses (2007)
  • Author(s): Uchiyama Y
  • Organizer: Neuroscience
  • Place of Presentation: in San Diego
  • Year and Date: 20071203-20071207
• [Presentation] Involvement of autophagy in neuron death of neonatal mouse brains after hypoxic-ischemic injury (2006)
  • Author(s): Uchiyama Y
  • Organizer: In: The 4th Internation Symposium of Autophagy
  • Place of Presentation: in Mishima
  • Year and Date: 20061001-20061005
• [Presentation] Roles of lysosomal proteinases in autophagic cell death (2005)
  • Author(s): Uchiyama Y
  • Organizer: 2005 Gordon Research Conference on "Autophagy in Stress, Development & Disease" in Il
  • Place of Presentation: Ciocco
  • Year and Date: 20050424-20050429
• [Presentation] Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten Disease) (2005)
  • Author(s): Uchiyama Y, Shibata M, Koike M
  • Organizer: International conference on serine-carboxyl peptidases and related enzymes
  • Place of Presentation: in Kyoto
  • Year and Date: 2005-11-10
• [Presentation] cathepsin D deficiency induces caspase dependent and independent neuron death (2004)
  • Author(s): Uchiyama Y
  • Organizer: Symp-55, 16th International congress of the IFAA
  • Year and Date: 20040822-20070827
• [Book] Molecular imaging for integrated medical therapy and drug development(Eds. Nagara Tamaki and Yuji Kuge, Autophagy and cell death) (2010)
  • Author(s): Uchiyama Y, Koike M, Shibata M
  • Total Pages: 176-188
  • Publisher: Springer Japan
• [Book] Methods Enzymol. Vol.453 (Autophagy in Disease and Clinical Applications, Part C)(Ed. Daniel J. Klionsky, Autophagic neuron death) (2009)
  • Author(s): Uchiyama Y, Koike M, Shibata M, Sasaki M
  • Total Pages: 33-51
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratorynabo/shinkei_kozo/index.html