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Eli Arama

Bio: Eli Arama is an academic researcher from Weizmann Institute of Science. The author has contributed to research in topics: Caspase & Apoptosis. The author has an hindex of 22, co-authored 35 publications receiving 8549 citations. Previous affiliations of Eli Arama include Rockefeller University & Howard Hughes Medical Institute.

Papers
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Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are 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 monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations

Journal ArticleDOI
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4  +183 moreInstitutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

3,301 citations

Journal Article
01 Jan 2018-Nature
TL;DR: An updated classification of cell death subroutines focusing on mechanistic and essential aspects of the process is proposed, and the utility of neologisms that refer to highly specialized instances of these processes are discussed.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

1,150 citations

Journal ArticleDOI
TL;DR: It is shown that apoptotic proteins play an essential role during spermatid individualization in Drosophila melanogaster, and that a giant ubiquitin-conjugating enzyme, dBruce, is required to protect the sperm nucleus against hypercondensation and degeneration.

407 citations

Journal ArticleDOI
TL;DR: It is shown that the effector caspases 6 and 3 are both expressed within axons and that, on trophic deprivation, they exhibit distinct modes of activation, indicating that two distinct autodestruction pathways act separately or in concert to regulate developmental neurite pruning.
Abstract: Selective degeneration of neuronal projections and neurite pruning are critical for establishment and maintenance of functional neural circuits in both insects and mammals However, the molecular mechanisms that govern developmental neurite pruning versus injury-induced neurite degeneration are still mostly unclear Here, we show that the effector caspases 6 and 3 are both expressed within axons and that, on trophic deprivation, they exhibit distinct modes of activation Surprisingly, inhibition of caspases is not sufficient for axonal protection and a parallel modulation of a NAD + -sensitive pathway is required The proapoptotic protein BAX is a key element in both pathways as its genetic ablation protected sensory axons against developmental degeneration both in vitro and in vivo Last, we demonstrate that both pathways are also involved in developmental dendritic pruning in Drosophila More specifically, the mouse Wld S (Wallerian degeneration slow) protein, which is mainly composed of the full-length sequence of the NAD + biosynthetic Nmnat1 enzyme, can suppress dendritic pruning in C4da (class IV dendritic arborization) sensory neurons in parallel to the fly effector caspases These findings indicate that two distinct autodestruction pathways act separately or in concert to regulate developmental neurite pruning

149 citations


Cited by
More filters
Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are 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 monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations

Journal ArticleDOI
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4  +183 moreInstitutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

3,301 citations

Journal ArticleDOI
TL;DR: The functional relationship between apoptosis and autophagy is complex in the sense that, under certain circumstances,autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway.
Abstract: The functional relationship between apoptosis ('self-killing') and autophagy ('self-eating') is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner. On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses.

3,200 citations

Journal ArticleDOI
TL;DR: A functional classification of cell death subroutines is proposed that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic programmed cell death, regulated necrosis, autophagic cell death and mitotic catastrophe.
Abstract: In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

2,238 citations

Journal ArticleDOI
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Lorenzo Galluzzi3, Stuart A. Aaronson4, John M. Abrams5, Emad S. Alnemri6, David W. Andrews7, Eric H. Baehrecke8, Nicolas G. Bazan9, Mikhail V. Blagosklonny10, Klas Blomgren11, Klas Blomgren12, Christoph Borner13, Dale E. Bredesen14, Dale E. Bredesen15, Catherine Brenner16, Maria Castedo1, Maria Castedo3, Maria Castedo2, John A. Cidlowski17, Aaron Ciechanover18, Gerald M. Cohen19, V De Laurenzi20, R De Maria21, Mohanish Deshmukh22, Brian David Dynlacht23, Wafik S. El-Deiry24, Richard A. Flavell25, Richard A. Flavell26, Simone Fulda27, Carmen Garrido2, Carmen Garrido28, Pierre Golstein2, Pierre Golstein29, Pierre Golstein16, Marie-Lise Gougeon30, Douglas R. Green, Hinrich Gronemeyer2, Hinrich Gronemeyer31, Hinrich Gronemeyer16, György Hajnóczky6, J. M. Hardwick32, Michael O. Hengartner33, Hidenori Ichijo34, Marja Jäättelä, Oliver Kepp2, Oliver Kepp1, Oliver Kepp3, Adi Kimchi35, Daniel J. Klionsky36, Richard A. Knight37, Sally Kornbluth38, Sharad Kumar, Beth Levine26, Beth Levine5, Stuart A. Lipton, Enrico Lugli17, Frank Madeo39, Walter Malorni21, Jean-Christophe Marine40, Seamus J. Martin41, Jan Paul Medema42, Patrick Mehlen16, Patrick Mehlen43, Gerry Melino19, Gerry Melino44, Ute M. Moll45, Ute M. Moll46, Eugenia Morselli2, Eugenia Morselli1, Eugenia Morselli3, Shigekazu Nagata47, Donald W. Nicholson48, Pierluigi Nicotera19, Gabriel Núñez36, Moshe Oren35, Josef M. Penninger49, Shazib Pervaiz50, Marcus E. Peter51, Mauro Piacentini44, Jochen H. M. Prehn52, Hamsa Puthalakath53, Gabriel A. Rabinovich54, Rosario Rizzuto55, Cecília M. P. Rodrigues56, David C. Rubinsztein57, Thomas Rudel58, Luca Scorrano59, Hans-Uwe Simon60, Hermann Steller61, Hermann Steller26, J. Tschopp62, Yoshihide Tsujimoto63, Peter Vandenabeele64, Ilio Vitale2, Ilio Vitale1, Ilio Vitale3, Karen H. Vousden65, Richard J. Youle17, Junying Yuan66, Boris Zhivotovsky67, Guido Kroemer2, Guido Kroemer3, Guido Kroemer1 
University of Paris-Sud1, French Institute of Health and Medical Research2, Institut Gustave Roussy3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, Boston Children's Hospital11, University of Gothenburg12, University of Freiburg13, University of California, San Francisco14, Buck Institute for Research on Aging15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Yale University25, Howard Hughes Medical Institute26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, Stony Brook University45, University of Göttingen46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells

2,218 citations