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  • 1.
    Klionsky, Daniel J.
    et al.
    University of Michigan, USA.
    Abeliovich, Hagai
    Hebrew University of Jerusalem, Israel.
    Agostinis, Patrizia
    Catholic University of Louvain, Belgium.
    Agrawal, Devendra K.
    Creighton University, USA.
    Aliev, Giumrakch
    University of Texas San Antonio, TX USA.
    S. Askew, David
    University of Cincinnati, USA.
    Baba, Misuzu
    Japan Womens University, Japan.
    H. Baehrecke, Eric
    University of Massachusetts, MA USA.
    A. Bahr, Ben
    University of Connecticut, CT USA.
    Ballabio, Andrea
    Telethon Institute Genet and Med, Italy.
    A. Bamber, Bruce
    University of Toledo, OH 43606 USA .
    C. Bassham, Diane
    Iowa State University, IA USA Iowa State University, IA USA .
    Bergamini, Ettore
    University of Pisa, Italy .
    Bi, Xiaoning
    Western University of Health Science, CA USA .
    Biard-Piechaczyk, Martine
    UM2, France .
    S. Blum, Janice
    Indiana University, IN 46202 USA .
    E. Breclesen, Dale
    Bucks Institute Age Research, CA USA .
    L. Brodsky, Jeffrey
    University of Pittsburgh, PA 15260 USA Massachusetts Gen Hospital, MA USA .
    H. Brumell, John
    Hospital Sick Children, Canada .
    Brunk, Ulf T.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bursch, Wilfried
    Medical University of Vienna, Austria .
    Camougrand, Nadine
    University of Bordeaux 2, France .
    Cebollero, Eduardo
    CSIC, Spain .
    Cecconi, Francesco
    University of Roma Tor Vergata, Italy University of Roma Tor Vergata, Italy .
    Chen, Yingyu
    Peking University, Peoples R China .
    Chin, Lih-Shen
    Emory University School of Medicine.
    Choi, Augustine
    Emory University, GA 30322 USA .
    T. Chu, Charleen
    Harvard University, MA USA.
    Chung, Jongkyeong
    University of Pittsburgh, PA USA Korea Adv Institute Science and Technology, South Korea .
    G. H. Clarke, Peter
    University of Lausanne, Switzerland .
    S. B. Clark, Robert
    Safar Centre Resuscitat Research, PA USA .
    G. Clarke, Steven
    University of Calif Los Angeles, CA 90024 USA University of Calif Los Angeles, CA 90024 USA .
    Clave, Corinne
    University of Bordeaux 2, France .
    L. Cleveland, John
    Scripps Research Institute, FL USA .
    Codogno, Patrice
    University of Paris 11, France INSERM, France .
    I. Colombo, Maria
    University of Nacl Cuyo, Argentina .
    Coto-Montes, Ana
    University of Oviedo, Spain .
    M. Cregg, James
    Keck Grad Institute Appl Science, CA USA .
    Maria Cuervo, Ana
    Albert Einstein Coll Med, NY 10467 USA .
    Debnath, Jayanta
    University of Calif San Francisco, CA USA .
    Demarchi, Francesca
    Lab Nazl Consorzio Interuniv Biotecnol, Italy University of Cincinnati, OH USA .
    B. Dennis, Patrick
    USN Medical Oncol, MD 20892 USA .
    A. Dennis, Phillip
    USN Medical Oncol, MD 20892 USA .
    Deretic, Vojo
    University of New Mexico, NM 87131 USA .
    J. Devenish, Rodney
    Monash University, Australia Monash University, Australia .
    Di Sano, Federica
    University of Roma Tor Vergata, Italy .
    Fred Dice, J.
    Tufts University, MA 02111 USA .
    DiFiglia, Marian
    Massachusetts Gen Hospital, MA USA .
    Dinesh-Kumar, Savithramma
    Yale University, CT USA .
    W. Distelhorst, Clark
    Case Western Reserve University, OH 44106 USA Case Western Reserve University, OH 44106 USA University Hospital Cleveland, OH 44106 USA Case Western Reserve University, OH 44106 USA .
    Djavaheri-Mergny, Mojgan
    University of Paris 11, France INSERM, France .
    C. Dorsey, Frank
    The Scripps Research Institute.
    Droege, Wulf
    Immunotec Research Ltd, Canada .
    Dron, Michel
    INRA, France .
    A. Jr. Dunn, William
    University of Florida, FL USA .
    Duszenko, Michael
    University of Tubingen, Germany .
    Tony Eissa, N.
    Baylor University, TX 77030 USA .
    Elazar, Zvulun
    Weizmann Institute Science, Israel .
    Esclatine, Audrey
    University of Paris 11, France INSERM, France .
    Eskelinen, Eeva-Liisa
    University of Helsinki, Finland .
    Fesues, Laszlo
    University of Debrecen, Hungary University of Debrecen, Hungary .
    D. Finley, Kim
    Salk Institute Biol Studies, CA USA .
    M. Fuentes, Jose
    University of Extremadura, Spain .
    Fueyo, Juan
    University of Texas Houston, TX 77030 USA .
    Fujisaki, Kozo
    Kagoshima University, Japan .
    Galliot, Brigitte
    University of Geneva, Switzerland .
    Gao, Fen-Biao
    University of Calif San Francisco, CA 94143 USA University of Calif San Francisco, CA 94143 USA .
    A. Gewirtz, David
    Virginia Commonwealth University, VA USA Virginia Commonwealth University, VA USA .
    B. Gibson, Spencer
    Manitoba Institute Cell Biol, Canada .
    Gohla, Antje
    University of Dusseldorf, Germany .
    L. Goldberg, Alfred
    Harvard University, MA USA .
    Gonzalez, Ramon
    CSIC, Spain .
    Gonzalez-Estevez, Cristina
    University of Nottingham, England .
    Gorski, Sharon
    British Columbia Cancer Agency, Canada .
    A. Gottlieb, Roberta
    San Diego State University, CA 92182 USA .
    Haussinger, Dieter
    University of Dusseldorf, Germany .
    He, You-Wen
    Duke University, NC USA .
    Heidenreich, Kim
    University of Colorado, CO USA .
    A. Hill, Joseph
    University of Texas SW Medical Centre Dallas, TX 75390 USA .
    Hoyer-Hansen, Maria
    Danish Cancer Soc, Denmark Danish Cancer Soc, Denmark .
    Hu, Xun
    Zhejiang University, Peoples R China .
    Huang, Wei-Pang
    National Taiwan University, Taiwan .
    Iwasaki, Akiko
    Yale University, CT USA .
    Jaattela, Marja
    University of Debrecen, Hungary University of Debrecen, Hungary .
    T. Jackson, William
    Medical Coll Wisconsin, WI 53226 USA .
    Jiang, Xuejun
    Mem Sloan Kettering Cancer Centre, NY 10021 USA .
    Jin, Shengkan
    University of Medical and Dent New Jersey, NJ 08854 USA .
    Johansen, Terje
    University of Tromso, Norway .
    U. Jung, Jae
    University of So Calif, CA USA .
    Kadowaki, Motoni
    Niigata University, Japan .
    Kang, Chanhee
    University of Texas SW Medical Centre Dallas, TX 75390 USA .
    Kelekar, Ameeta
    University of Minnesota, MN USA .
    H. Kessel, David
    Wayne State University, MI USA .
    A. K. W. Kiel, Jan
    University of Groningen, Netherlands .
    Pyo Kim, Hong
    University of Pittsburgh, PA USA .
    Kimchi, Adi
    Weizmann Institute Science, Israel .
    J. Kinsella, Timothy
    University Hospital Cleveland, OH 44106 USA .
    Kiselyov, Kirill
    University of Pittsburgh, PA 15260 USA .
    Kitamoto, Katsuhiko
    University of Tokyo, Japan .
    Knecht, Erwin
    Centre Invest Principe Felipe, Spain .
    Komatsu, Masaaki
    Tokyo Metropolitan Institute Medical Science, Japan .
    Kominami, Eiki
    Juntendo University, Japan .
    Kondo, Seiji
    University of Texas MD Anderson Cancer Center.
    L. Kovacs, Attila
    University of Texas MD Anderson Cancer Centre, TX USA .
    Kroemer, Guido
    Eotvos Lorand University, Hungary Institute Gustave Roussy, France University of Paris 11, France .
    Kuan, Chia-Yi
    Cincinnati Childrens Hospital Research Fdn, OH USA .
    Kumar, Rakesh
    University of Penn, PA 19104 USA .
    Kundu, Mondira
    University of Laval, Canada .
    Landry, Jacques
    Eastern Michigan University, MI 48197 USA .
    Laporte, Marianne
    Eastern Michigan University.
    Le, Weidong
    Shanghai Jiao Tong University, Peoples R China Chinese Academic Science, Peoples R China .
    Lei, Huan-Yao
    National Cheng Kung University, Taiwan .
    J. Lenardo, Michael
    NIAID, MD USA .
    Levine, Beth
    University of Texas SW Medical Centre Dallas, TX 75390 USA University of Texas SW Medical Centre Dallas, TX 75390 USA .
    Lieberman, Andrew
    University of Michigan, MI USA .
    Lim, Kah-Leong
    National Institute Neurosci, Singapore .
    Lin, Fu-Cheng
    Zhejiang University, Peoples R China .
    Liou, Willisa
    Chang Gung University.
    F. Liu, Leroy
    University of Medical and Dent New Jersey, NJ 08854 USA National Research Centre Environm and Heatlh, Germany .
    Lopez-Berestein, Gabriel
    University of Texas MD Anderson Cancer Centre, TX USA .
    Lopez-Otin, Carlos
    University of Oviedo, Spain .
    Lu, Bo
    Vanderbilt University, TN USA .
    F. Macleod, Kay
    University of Chicago, IL 60637 USA Ist Super Sanita, Italy .
    Malorni, Walter
    Istituto Superiore di Sanita.
    Martinet, Wim
    University of Antwerp, Belgium .
    Matsuoka, Ken
    Kyushu University, Japan .
    Mautner, Josef
    GSF-National Research Center for Environment and Health.
    J. Meijer, Alfred
    University of Amsterdam, Netherlands .
    Melendez, Alicia
    CUNY, NY USA .
    Michels, Paul
    Catholic University of Louvain, Belgium Catholic University of Louvain, Belgium .
    Miotto, Giovanni
    University of Padua, Italy .
    P. Mistiaen, Wilhelm
    University of Coll Antwerp, Belgium .
    Mizushima, Noboru
    Tokyo Medical and Dent University, Japan .
    Mograbi, Baharia
    INSERM, France IFR 50, France .
    Monastyrska, Iryna
    University of Utrecht, Netherlands .
    N. Moore, Michael
    Plymouth Marine Lab, England .
    I. Moreira, Paula
    Centre Neurosci and Cell Biol, Portugal .
    Moriyasu, Yuji
    Saitama University, Japan .
    Motyl, Tomasz
    Agriculture University of Warsaw, Poland .
    Muenz, Christian
    Rockefeller University, NY 10021 USA .
    O. Murphy, Leon
    Novartis Institute Biomed Research, MA USA .
    I. Naqvi, Naweed
    National University of Singapore, Singapore .
    Neufeld, Thomas
    University of Minnesota.
    Nishino, Ichizo
    National Centre Neurol and Psychiat, Japan .
    A. Nixon, Ralph
    NYU, NY USA .
    Noda, Takeshi
    Osaka University, Japan .
    Nuernberg, Bernd
    University of Dusseldorf, Germany .
    Ogawa, Michinaga
    University of Tokyo, Japan .
    L. Oleinick, Nancy
    Case Western Reserve University, OH USA Case Western Reserve University, OH 44106 USA Case Western Reserve University, OH 44106 USA Case Western Reserve University, OH 44106 USA .
    J. Olsen, Laura
    University of Michigan, MI 48109 USA .
    Ozpolat, Bulent
    University of Texas MD Anderson Cancer Centre, TX USA .
    Paglin, Shoshana
    Chaim Sheba Medical Centre, Israel .
    E. Palmer, Glen
    Louisiana State University, LA USA .
    Papassideri, Issidora
    Department Cell Biol and Biophys, Greece .
    Parkes, Miles
    University of Cambridge, England .
    H. Perlmutter, David
    University of Pittsburgh, PA 15261 USA Childrens Hospital Pittsburgh, PA 15213 USA .
    Perry, George
    University of Texas San Antonio, TX USA .
    Piacentini, Mauro
    University of Roma Tor Vergata, Italy .
    Pinkas-Kramarski, Ronit
    Tel Aviv University, Israel .
    Prescott, Mark
    Monash University, Australia .
    Proikas-Cezanne, Tassula
    University of Tubingen, Germany .
    Raben, Nina
    NIAMSD, MD USA .
    Rami, Abdelhaq
    Clin JWG University, Germany .
    Reggiori, Fulvio
    University of Utrecht, Netherlands .
    Rohrer, Baerbel
    Medical University of S Carolina, SC 29425 USA .
    C. Rubinsztein, David
    Cambridge Institute Medical Research, England .
    M. Ryan, Kevin
    Beatson Institute Cancer Research, Scotland .
    Sadoshima, Junichi
    University of Medical and Dent New Jersey, NJ 07103 USA .
    Sakagami, Hiroshi
    Meikai University, Japan .
    Sakai, Yasuyoshi
    Kyoto University, Japan JST, Japan .
    Sandri, Marco
    University of Padua, Italy Venetan Institute Molecular Med, Italy .
    Sasakawa, Chihiro
    University of Tokyo, Japan .
    Sass, Miklos
    University of Oslo, Norway .
    Schneider, Claudio
    Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie.
    O. Seglen, Per
    University of Wyoming, WY 82071 USA .
    Seleverstov, Oleksandr
    University of Oslo, Norway .
    Settleman, Jeffre
    Massachusetts General Hospital Cancer Center.
    J. Shacka, John
    University of Alabama Birmingham, AL 35294 USA .
    M. Shapiro, Irving
    Thomas Jefferson University, PA 19107 USA .
    Sibirny, Andrei
    National Academic Science Ukraine, Ukraine .
    C. M. Silva-Zacarin, Elaine
    University of Federal Sao Carlos, Brazil .
    Simon, Hans-Uwe
    University of Bern, Switzerland .
    Simone, Cristiano
    Ist Ric Farmacol Mario Negri, Italy .
    Simonsen, Anne
    University of Oslo, Norway Norwegian Radium Hospital, Norway .
    A. Smith, Mark
    Case Western Reserve University, OH 44106 USA .
    Spanel-Borowski, Katharina
    University of Leipzig, Germany .
    Srinivas, Vickram
    Thomas Jefferson University, PA 19107 USA .
    Steeves, Meredith
    Scripps Research Institute, FL USA .
    Stenmark, Harald
    Norwegian Radium Hospital, Norway .
    E. Stromhaug, Per
    University of Missouri, MO USA .
    S. Subauste, Carlos
    Case Western Reserve University, OH USA Case Western Reserve University, OH USA .
    Sugimoto, Seiichiro
    National Hospital Org, Japan .
    Sulzer, David
    Columbia University, NY USA Columbia University, NY USA .
    Suzuki, Toshihiko
    University of Ryukyus, Japan .
    S. Swanson, Michele
    University of Michigan, MI 48109 USA .
    Takeshita, Fumihiko
    Yokohama City University, Japan .
    J. Talbot, Nicholas.
    University of Exeter, England .
    Talloczy, Zsolt
    Columbia University, NY USA Columbia University, NY USA .
    Tanaka, Keiji
    Tokyo Metropolitan Institute Medical Science, Japan Tohoku University, Japan .
    Tanaka, Kozo
    Tokyo Metropolitan Institute Medical Science, Japan Tohoku University, Japan .
    Tanida, Isei
    National Institute Infect Disease, Japan .
    S. Taylor, Graham
    University of Birmingham, England .
    Paul Taylor, J.
    University of Penn, PA 19104 USA .
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Tettamanti, Gianluca
    University of Insubria, Italy .
    B. Thompson, Craig
    University of Penn, PA 19104 USA .
    Thumm, Michael
    University of Gottingen, Germany .
    M. Tolkovsky, Aviva
    University of Cambridge, England .
    A. Tooze, Sharon
    Cancer Research UK London Research Institute, England .
    Truant, Ray
    McMaster University, Canada .
    V. Tumanovska, Lesya
    AA Bogomolets Physiol Institute, Ukraine .
    Uchiyama, Yasuo
    Osaka University, Japan .
    Ueno, Takashi
    Juntendo University, Japan .
    L. Uzcategui, Nestor
    Central University of Venezuela, Venezuela .
    van der Klei, Ida
    University of Groningen, Netherlands .
    C. Vaquero, Eva
    Hospital Clin Barcelona, Spain .
    Vellai, Tibor
    Eotvos Lorand University, Hungary .
    W. Vogel, Michael
    Maryland Psychiat Research Centre, MD 21228 USA .
    Wang, Hong-Gang
    H Lee Moffitt Cancer Centre and Research Institute, FL USA .
    Webster, Paul
    House Ear Research Institute, CA USA .
    W. Wiley, John
    University of Michigan, MI 48109 USA .
    Xi, Zhijun
    Peking University, Peoples R China .
    Xiao, Gutian
    University of Pittsburgh, PA USA .
    Yahalom, Joachim
    Memorial Sloan-Kettering Cancer Center.
    Yang, Jin-Ming
    University of Medical and Dent New Jersey, NJ USA .
    Yap, George
    University of Medical and Dent New Jersey, NJ 07103 USA .
    Yin, Xiao-Min
    University of Pittsburgh, PA USA .
    Yoshimori, Tamotsu
    Osaka University, Japan .
    Yu, Li
    NIAID, MD USA .
    Yue, Zhenyu
    Mt Sinai School Med, NY USA .
    Yuzaki, Michisuke
    Keio University, Japan .
    Zabirnyk, Olga
    NCI, MD USA National Institute Heatlh, MD USA .
    Zheng, Xiaoxiang
    Zhejiang University, Peoples R China .
    Zhu, Xiongwei
    Case Western Reserve University, OH 44106 USA .
    L. Deter, Russell
    Baylor University, TX 77030 USA .
    Tabas, Ira
    Columbia University, NY USA .
    Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes2008In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 4, no 2, p. 151-175Article, review/survey (Refereed)
    Abstract [en]

    Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.

  • 2.
    Klionsky, Daniel J.
    et al.
    University of Michigan, Department of Molecular, Cellular, and Developmental Biology, Ann Arbor, MI, USA; University of Michigan, Life Sciences Institute, Ann Arbor, MI, USA .
    Boman, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Zughaier, Susu M.
    Emory University, School of Medicine, Department of Microbiology and Immunology, Atlanta, GA, USA.
    Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)2016In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 2, no 1, p. 1-222Article, review/survey (Refereed)
  • 3.
    Ullio, Chiara
    et al.
    University of Turin, Italy.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Urani, Chiara
    University of Milano Bicocca, Italy.
    Melchioretto, Pasquale
    University of Milano Bicocca, Italy.
    Bonelli, Gabriella
    University of Turin, Italy.
    Baccino, Francesco M.
    University of Turin, Italy.
    Autelli, Riccardo
    University of Turin, Italy.
    Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells2015In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 11, no 12, p. 2184-2198Article in journal (Refereed)
    Abstract [en]

    Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other iron-binding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

  • 4.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Terman, Alexi
    Karolinska University Hospital, Stockholm.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Dehvari, Nodi
    Karolinska Institutet, Stockholm.
    Cowburn, Richard F.
    AstraZeneca, Södertälje.
    Benedikz, Eirikur
    Karolinska Institutet.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Cedazo-Minguez, Angel
    Karolinska Institutet.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells2011In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 7, no 12, p. 1528-1545Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days, and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide aditional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

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