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1. Gaia Early Data Release 3: Acceleration of the solar system from Gaia astrometry

Author

Vincenzo Ripepi, P. Gavras, M. Vaillant, Mathias Schultheis, László Molnár, E. Poujoulet, Mark Cropper, C. Babusiaux, D. Molina, J. Fernández-Hernández, G. Jevardat de Fombelle, A. de Torres, Aldo Dell'Oro, J. Castañeda, Z. Kostrzewa-Rutkowska, A. Bombrun, André Moitinho, Marcella Marconi, Rossella Cancelliere, M. Hauser, M. Ajaj, C. M. Raiteri, L. Eyer, Michał Pawlak, H. I. Siddiqui, C. Ducourant, Tatiana Muraveva, Tsevi Mazeh, A. Panahi, Federico Marocco, Stefano Bertone, D. Vicente, Patrick Charlot, A. Guerrier, R. De March, Mario Gai, J. Souchay, H. E. P. Lindstrøm, Nicoletta Sanna, Agnes Fienga, Giovanni Comoretto, Jon Marchant, A. Lorca, E. Utrilla, A. Garcia-Gutierrez, Ilaria Musella, L. Balaguer-Núñez, Leanne P. Guy, N. Leclerc, E. Brugaletta, A. Yoldas, Harry Enke, Rosanna Sordo, Zoltan Balog, H. E. Huckle, L. Palaversa, Monica Rainer, T. A. Lister, F. A. Jansen, Ruth Carballo, Alessandro Spagna, J. M. Carrasco, Mikael Granvik, Derek W. Morris, F. Julbe, A. Hutton, J. Osinde, D. W. Evans, M. van Leeuwen, M. Weiler, F. Thévenin, F. Torra, Iain A. Steele, Lorenzo Rimoldini, Alessandro Sozzetti, Francesca Fragkoudi, K. Janßen, O. L. Creevey, J. González-Núñez, T. Pauwels, R. Buzzi, Miguel García-Torres, S. Liao, G. Tauran, Lennart Lindegren, C. Fouron, Pierre Fernique, Céline Reylé, P. Di Matteo, E. Szegedi-Elek, F. Pailler, Stefan Jordan, Roberto Molinaro, Elisabetta Caffau, Federica Spoto, Felix Franke, D. Barbato, Isabelle Lecoeur-Taïbi, Tristan Cantat-Gaudin, Alejandra Recio-Blanco, E. Livanou, W. Roux, X. Peñalosa Esteller, P. A. Palicio, J. H. J. de Bruijne, Sergi Blanco-Cuaresma, Deborah Busonero, F. Riclet, Conny Aerts, Georges Kordopatis, Guy Rixon, F. Solitro, Davide Massari, Mike Smith, D. Baines, Roberto Morbidelli, Gerry Gilmore, G. Plum, Alexey Mints, O. Marchal, Juan Zorec, Ángel Gómez, C. A. Stephenson, Michael Davidson, C. Fabricius, E. Licata, Sergio Messina, Laszlo Szabados, M. Biermann, A. Garofalo, G. Holland, F. De Angeli, Andreas Korn, E. Anglada Varela, Grigori Fedorets, S. Girona, E. Gerlach, Antonella Vallenari, M. Riello, Łukasz Wyrzykowski, Damien Ségransan, F. Taris, L. Bramante, Alberto Cellino, S. Regibo, Andrej Prsa, M. Sarasso, E. Poggio, W. Löffler, Paolo Giacobbe, Jordi Portell, Elisa Distefano, Eric Slezak, I. Bellas-Velidis, Nicolas Rambaux, E. Balbinot, J.-B. Delisle, Maroussia Roelens, E. Salguero, P. de Teodoro, E. van Dillen, Y. Lebreton, Francois Mignard, Sergei A. Klioner, Ulrich Bastian, N. Samaras, G. Orrù, R. E. de Souza, P. Esquej, Paul J. McMillan, A. C. Lanzafame, Sébastien Lambert, Beatrice Bucciarelli, Jose M Hernandez, M. Bernet, S. Ragaini, Gisella Clementini, A. F. Mulone, Ludovic Delchambre, C. Panem, Eric Gosset, P. David, M. Garcia-Reinaldos, Ana Ulla, F. Crifo, J. Guiraud, Mariateresa Crosta, L. Chaoul, C. Diener, Carlos Dafonte, Karri Muinonen, Alex Lobel, J.-L. Bassilana, Maria Süveges, Isabella Pagano, Dimitri Pourbaix, D. Eappachen, M. Haywood, R. Drimmel, Y. Viala, S. Voutsinas, D. Semeux, William Thuillot, N. A. Walton, Paolo Montegriffo, A. Abreu Aramburu, C. Fabre, H. Zhao, Alessandro Bressan, S. Bouquillon, Sanjeev Khanna, T. Lebzelter, N. Tonello, L. Siltala, M. G. Lattanzi, C. Crowley, P. Yvard, Carme Jordi, Elena Pancino, E. del Pozo, Jan Rybizki, Nami Mowlavi, C. Barache, Morgan Fouesneau, J. De Ridder, Ugo Becciani, Martin Altmann, F. van Leeuwen, P. M. Marrese, M. A. Álvarez, A. Jean-Antoine Piccolo, A. F. Lanza, Alberto Vecchiato, Thomas Wevers, Caroline Soubiran, C. P. Murphy, A. M. Piersimoni, Alessandra Mastrobuono-Battisti, Peter G. Jonker, A. Sagristà Sellés, T. Roegiers, S. Marinoni, Johannes Sahlmann, Rene Andrae, P. Sartoretti, G. Altavilla, Raphael Guerra, F. X. Pineau, M. Segol, T. Prusti, J. J. González-Vidal, J. J. Aguado, N. R. Millar, A. Baudesson-Stella, Andrea Chiavassa, Laurent Chemin, C. Turon, H. Steidelmüller, Douglas J. Marshall, A. G. Butkevich, Alberto Riva, P. de Laverny, Simchon Faigler, Laurent Galluccio, A. Mora, P. Re Fiorentin, C. Ordénovic, J. F. Le Campion, A. Delgado, V. Sanchez Gimenez, M. David, G. Sadowski, R. L. Smart, A. Masip, Laia Casamiquela, R. Messineo, R. Mor, J. Bakker, C. Dolding, J. M. Martín-Fleitas, S. Diakite, Coryn A. L. Bailer-Jones, D. Souami, P. Madrero Pardo, Martin A. Barstow, David Teyssier, Ummi Abbas, Jesus Salgado, Paolo Tanga, A. Burlacu, O. Vanel, Ulrike Heiter, Daniel Hestroffer, Sebastian L. Hidalgo, H. E. Delgado, Alberto Krone-Martins, C. Robin, Kevin Benson, Christos Siopis, S. Managau, P. Burgess, Tomaz Zwitter, M. M. S. Marcos Santos, S. Cowell, J. L. Halbwachs, Xavier Luri, Antti Penttilä, R. Geyer, Minia Manteiga, Yassine Damerdji, Nigel Hambly, S. Bartolomé, J. Álvarez Cid-Fuentes, P. Osborne, J. Juaristi Campillo, Mark Taylor, Richard I. Anderson, Y. Le Fustec, Thierry Morel, T. Cornez, Krzysztof A. Rybicki, L. Pulone, N. Bauchet, Pierre Kervella, C. Zurbach, Alfred Castro-Ginard, Frédéric Arenou, P. Ramos, Robert G. Mann, Annie C. Robin, J. C. Segovia, M. Barros, Hector Canovas, D. L. Harrison, Y. Lasne, L. Noval, David Hobbs, E. F. del Peloso, P. Castro Sampol, Yves Fremat, F. De Luise, Daniel Michalik, P. J. Richards, L. Karbevska, N. Hładczuk, K. Kruszyńska, T. Boch, Sofia Randich, A. G. A. Brown, C. Pagani, L. Martin Polo, M. Ramos-Lerate, Krzysztof Nienartowicz, Eduard Masana, E. Racero, E. Fraile, Marc Audard, N. Robichon, Luciana Bianchi, G. Gracia-Abril, R. Santoveña, R. Haigron, N. Unger, Jérôme Berthier, Despina Hatzidimitriou, R. Gutiérrez-Sánchez, M. Fabrizio, I. Gonzalez-Santamaria, A. Dapergolas, P. Panuzzo, Benoit Carry, Francesca Figueras, R. Blomme, Elmé Breedt, D. Munoz, Diego Bossini, G. Busso, D. Katz, Simon Hodgkin, Ennio Poretti, N. Brouillet, Marco Castellani, Nicholas Rowell, Arnaud Siebert, M. Romero-Gómez, Shay Zucker, W. van Reeven, A. Kochoska, G. Giuffrida, Eva Sciacca, T. Carlucci, L. M. Sarro, M. I. Carnerero, Amina Helmi, D. Garabato, B. Holl, Michele Bellazzini, L. Rohrbasser, Teresa Antoja, J. Torra, Thomas Hilger, Pedro García-Lario, Gérard Jasniewicz, Enrique Solano, S. G. Baker, W. J. Cooper, F. Royer, S. Accart, George M. Seabroke, João Alves, Emese Plachy, C. Nicolas, Silvio Leccia, N. Cheek, Uwe Lammers, Ramachrisna Teixeira, Techniche Universtât Desden, Joseph Louis LAGRANGE (LAGRANGE), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Lund Observatory, Lund University [Lund], Zentrum für astronomie, Universität Heidelberg [Heidelberg], Department of nuclear medicine, Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB), Merck Serono S.A [Geneva Research Center], Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA (UMR_8109)), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Physique de Rennes (IPR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg] = Heidelberg University, Laboratoire d'études spatiales et d'instrumentation en astrophysique = Laboratory of Space Studies and Instrumentation in Astrophysics (LESIA), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Planetary-system research, Department of Physics, Particle Physics and Astrophysics, Gaia Collaboration, Unidad de Excelencia Científica María de Maeztu Instituto de Ciencias del Cosmos Universidad de Barcelona, MDM-2014-0369, Centro de Excelencia Científica Severo Ochoa, Instituto de Ciencias del Cosmos de la Universidad de Barcelona, SEV2015-0493, Deliste, J. B. [0000-0001-5844-9888], Sozzeti, A. [0000-0002-7504-365X], Forderung der wissenschaftlichen Forschung (FWF), Belgian federal Science Policy Office (BELSPO), Hertha Firnberg Programme, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Comite Francais d'Evaluation de la Cooperation Universitaire et Scientifique avec le Bresil (COFECUB), National Natural Science Foundation of China (NSFC), China Scholarship Council (CSC), European Commission (EC), European Research Council (ERC), Hungarian National Research, Development, and Innovation Office (NKFIH), Science Foundation Ireland (SFI), Israel Science Foundation (ISF), Agenzia Spaziale Italiana (ASI), Istituto Nazionale di Astrofisica (INAF), Netherlands Research School for Astronomy (NOVA), Fundacao para a Ciencia e a Tecnologia (FCT), Agencia Estatal de Investigación (AEI), European Space Agency (ESA), Centre National D'Etudes Spatiales (CNES), Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), Narodowe Centrum Nauki (NCN), Slovenian Research Agency, Swedish National Space Agency (SNSA), United Kingdom Science and Technology Facilities Council (STFC), Universitat de Barcelona (UB), Generalitat de Catalunya, Xunta de Galicia, Universidad de Cantabria, ITA, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Astronomy, and Kapteyn Astronomical Institute

Subjects
Data Analysis, Solar System, Astronomy, kinematics and dynamics, virgo cluster, Astrophysics, 01 natural sciences, bar, Astronomi, astrofysik och kosmologi, large-magellanic-cloud, Methods, Astronomy, Astrophysics and Cosmology, 010303 astronomy & astrophysics, Physics, Astrophysics of Galaxies, [SDU.ASTR]Sciences of the Universe [physics]/Astrophysics [astro-ph], Astrophysics::Instrumentation and Methods for Astrophysics, Astrometry, VIRGO CLUSTER, Kinematics and Dynamics, Amplitude, kinematics, Physical Sciences, MILKY-WAY, astrometry, Galaxy: kinematics and dynamics, PROPER MOTION, Proper motion, perturbation, proper motions, reference systems, methods: data analysis, Astrophysics - Astrophysics of Galaxies, FOS: Physical sciences, Context (language use), proper motion, Astronomy & Astrophysics, MASS, Computer Science::Digital Libraries, Gravitational potential, Acceleration, Settore FIS/05 - Astronomia e Astrofisica, 0103 physical sciences, data analysis [methods], Vector spherical harmonics, KINEMATICS, distance, milky-way, Science & Technology, PERTURBATION, 010308 nuclear & particles physics, Astronomy and Astrophysics, kinematics and dynamics [Galaxy], 115 Astronomy, Space science, Physics::History of Physics, BAR, Galaxy, Space and Planetary Science, [SDU]Sciences of the Universe [physics], Astrophysics of Galaxies (astro-ph.GA), DISTANCE, mass, LARGE-MAGELLANIC-CLOUD
Abstract

Context. Gaia Early Data Release 3 (Gaia EDR3) provides accurate astrometry for about 1.6 million compact (QSO-like) extragalactic sources, 1.2 million of which have the best-quality five-parameter astrometric solutions., Aims. The proper motions of QSO-like sources are used to reveal a systematic pattern due to the acceleration of the solar systembarycentre with respect to the rest frame of the Universe. Apart from being an important scientific result by itself, the acceleration measured in this way is a good quality indicator of the Gaia astrometric solution., Methods. Theeffect of the acceleration was obtained as a part of the general expansion of the vector field of proper motions in vector spherical harmonics (VSH). Various versions of the VSH fit and various subsets of the sources were tried and compared to get the most consistent result and a realistic estimate of its uncertainty. Additional tests with the Gaia astrometric solution were used to get a better idea of the possible systematic errors in the estimate., Results. Our best estimate of the acceleration based on Gaia EDR3 is (2.32 +/- 0.16) x 10(-10) m s(-2) (or 7.33 +/- 0.51 km s(-1) Myr-1) towards alpha = 269.1 degrees +/- 5.4 degrees, delta = -31.6 degrees +/- 4.1 degrees, corresponding to a proper motion amplitude of 5.05 +/- 0.35 mu as yr(-1). This is in good agreement with the acceleration expected from current models of the Galactic gravitational potential. We expect that future Gaia data releases will provide estimates of the acceleration with uncertainties substantially below 0.1 mu as yr(-1).

Published
2020
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2. BAX channel activity mediates lysosomal disruption linked to Parkinson disease

Author

Agnes Bombrun, Benjamin Dehay, Marta Martinez-Vicente, Miquel Vila, Celine Perier, Bruno Antonsson, Jordi Bové, Ariadna Recasens, Neurodegenerative Diseases Research Group (CIBERNED), Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases, Merck Serono S.A [Geneva Research Center], Institució Catalana de Recerca i Estudis Avançats (ICREA), and Dehay, Benjamin

Subjects
Autophagosome, Male, [SDV]Life Sciences [q-bio], Mitochondrion, Ion Channels, Permeability, chemistry.chemical_compound, Mice, Bcl-2-associated X protein, Lysosome, BAX channel inhibitor, medicine, Neurotoxin, Animals, Humans, Molecular Biology, Cells, Cultured, MPTP, bcl-2-Associated X Protein, biology, Neurodegeneration, Autophagy, neurodegeneration, Brain, Cell Biology, Intracellular Membranes, medicine.disease, Basic Research Paper, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Parkinson disease, mitochondria, Protein Transport, medicine.anatomical_structure, chemistry, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, biology.protein, lysosome, Lysosomes
Abstract

International audience; Lysosomal disruption is increasingly regarded as a major pathogenic event in Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased levels of lysosomal-associated proteins and accumulation of undegraded autophagosomes (AP) are observed in PD-derived samples, including fibroblasts, induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain tissue. Mechanistic studies in toxic and genetic rodent PD models attribute PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization (LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent lysosomal defects remain virtually unknown, thereby precluding their potential therapeutic targeting. Here we show that the pro-apoptotic protein BAX (BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD models and is activated in PD patients, translocates and internalizes into lysosomal membranes early following treatment with the parkinsonian neurotoxin MPTP, both in vitro and in vivo, within a time-frame correlating with LMP, lysosomal disruption, and autophagosome accumulation and preceding mitochondrial permeabilization and dopaminergic neurodegeneration. Supporting a direct permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to induce LMP in purified mouse brain lysosomes and the latter can be prevented by pharmacological blockade of BAX channel activity. Furthermore, pharmacological BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse AP accumulation, and attenuate mitochondrial permeabilization and overall nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall, our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP, and point to small molecules able to block BAX channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.

Published
2014
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3. A sandwich ELISA for the conformation-specific quantification of the activated form of human Bax.

Author

Teijido O, Ganesan YT, Llanos R, Peton A, Urtecho JB, Soprani A, Villamayor A, Antonsson B, Manon S, and Dejean L

Subjects
Apoptosis, HeLa Cells, Humans, Mitochondrial Membranes chemistry, Permeability, Protein Conformation, Enzyme-Linked Immunosorbent Assay methods, bcl-2-Associated X Protein analysis
Abstract

Bcl-2 family proteins are critical regulators of mitochondrial outer membrane permeabilization (MOMP), which represents the point of no return of apoptotic cell death. The exposure of the Bax N-terminus at the mitochondria reflects Bax activation; and this activated configuration of the Bax protein is associated with MOMP. N-terminal exposure can be detected using specific monoclonal and/or polyclonal antibodies, and the onset of activated Bax has extensively been used as an early marker of apoptosis. The protocols of immunoprecipitation and/or immunocytochemistry commonly used to detect activated Bax are long and tedious, and allow semiquantification of the antigen at best. The sandwich ELISA protocol we developed has a 5 ng/mL detection limit and is highly specific for the activated conformation of Bax. This ELISA allows a rapid quantification of activated human Bax in whole cells and isolated mitochondria protein extracts. These properties grant this assay the potential to further clarify the prognostic and diagnostic value of activated Bax in disorders associated with deregulated apoptotic pathways such as degenerative diseases or cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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4. Bcl-xL stimulates Bax relocation to mitochondria and primes cells to ABT-737.

Author

Renault TT, Teijido O, Missire F, Ganesan YT, Velours G, Arokium H, Beaumatin F, Llanos R, Athané A, Camougrand N, Priault M, Antonsson B, Dejean LM, and Manon S

Subjects
Animals, Apoptosis, Cell Line, Mice, Piperazines pharmacology, Protein Multimerization, Protein Transport, Saccharomyces cerevisiae, Antineoplastic Agents pharmacology, Biphenyl Compounds pharmacology, Mitochondria metabolism, Nitrophenols pharmacology, Sulfonamides pharmacology, bcl-2-Associated X Protein metabolism, bcl-X Protein metabolism
Abstract

Bax cytosol-to-mitochondria translocation is a central event of the intrinsic pathway of apoptosis. Bcl-xL is an important regulator of this event and was recently shown to promote the retrotranslocation of mitochondrial Bax to the cytosol. The present study identifies a new aspect of the regulation of Bax localization by Bcl-xL: in addition to its role in Bax inhibition and retrotranslocation, we found that, like with Bcl-2, an increase of Bcl-xL expression levels led to an increase of Bax mitochondrial content. This finding was substantiated both in pro-lymphocytic FL5.12 cells and a yeast reporting system. Bcl-xL-dependent increase of mitochondrial Bax is counterbalanced by retrotranslocation, as we observed that Bcl-xLΔC, which is unable to promote Bax retrotranslocation, was more efficient than the full-length protein in stimulating Bax relocation to mitochondria. Interestingly, cells overexpressing Bcl-xL were more sensitive to apoptosis upon treatment with the BH3-mimetic ABT-737, suggesting that despite its role in Bax inhibition, Bcl-xL also primes mitochondria to permeabilization and cytochrome c release., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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5. BAX channel activity mediates lysosomal disruption linked to Parkinson disease.

Author

Bové J, Martínez-Vicente M, Dehay B, Perier C, Recasens A, Bombrun A, Antonsson B, and Vila M

Subjects
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Animals, Brain metabolism, Brain pathology, Cells, Cultured, Humans, Intracellular Membranes drug effects, Intracellular Membranes metabolism, Ion Channels drug effects, Lysosomes drug effects, Male, Mice, Mice, Inbred C57BL, Parkinson Disease pathology, Permeability drug effects, Protein Transport drug effects, bcl-2-Associated X Protein metabolism, Ion Channels metabolism, Lysosomes metabolism, Parkinson Disease metabolism, bcl-2-Associated X Protein physiology
Abstract

Lysosomal disruption is increasingly regarded as a major pathogenic event in Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased levels of lysosomal-associated proteins and accumulation of undegraded autophagosomes (AP) are observed in PD-derived samples, including fibroblasts, induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain tissue. Mechanistic studies in toxic and genetic rodent PD models attribute PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization (LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent lysosomal defects remain virtually unknown, thereby precluding their potential therapeutic targeting. Here we show that the pro-apoptotic protein BAX (BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD models and is activated in PD patients, translocates and internalizes into lysosomal membranes early following treatment with the parkinsonian neurotoxin MPTP, both in vitro and in vivo, within a time-frame correlating with LMP, lysosomal disruption, and autophagosome accumulation and preceding mitochondrial permeabilization and dopaminergic neurodegeneration. Supporting a direct permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to induce LMP in purified mouse brain lysosomes and the latter can be prevented by pharmacological blockade of BAX channel activity. Furthermore, pharmacological BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse AP accumulation, and attenuate mitochondrial permeabilization and overall nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall, our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP, and point to small molecules able to block BAX channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.

Published
2014
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6. Treatment with atacicept enhances neuronal cell death in a rat model of optic neuritis.

Author

Kretzschmar B, Hein K, Moinfar Z, Könnecke B, Sättler MB, Hess H, Weissert R, and Bähr M

Subjects
Animals, Apoptosis drug effects, Cell Death drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Immunohistochemistry, Neurons pathology, Rats, Rats, Inbred BN, Recombinant Fusion Proteins administration & dosage, Retinal Ganglion Cells pathology, Neurons drug effects, Optic Neuritis pathology, Recombinant Fusion Proteins adverse effects, Retinal Ganglion Cells drug effects
Abstract

We investigated the effect of atacicept, a recombinant fusion protein blocking BLyS and APRIL and acting on B cells, on degeneration of retinal ganglion cells (RGCs) during experimental autoimmune encephalomyelitis (EAE). We used myelin oligodendrocyte glycoprotein in Brown Norway rats to induce a variant of EAE which involves B cells and leads to severe optic neuritis. Intraperitoneal treatment with atacicept at some of the studied dose levels (100 or 200 μg) resulted in increased apoptosis of retinal ganglion cells whereas at a tenfold lower dose or in vehicle-treated animals no such effect became apparent. Also the extent of inflammation, demyelination, and axonal loss of the optic nerve was more pronounced in rats treated with the higher atacicept dose level. The present study describes observational evidence for adverse effects of atacicept on neuronal survival during EAE., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Published
2014
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7. Purification and separation of the 20S immunoproteasome from the constitutive proteasome and identification of the subunits by LC-MS.

Author

Dechavanne V, Vilbois F, Glez L, and Antonsson B

Subjects
Blotting, Western, Caspases metabolism, Cell Line, Tumor, Chymotrypsin metabolism, Electrophoresis, Polyacrylamide Gel, Humans, Hydrophobic and Hydrophilic Interactions, Protein Subunits, Trypsin metabolism, Chromatography, Liquid methods, Mass Spectrometry methods, Proteasome Endopeptidase Complex chemistry, Proteasome Endopeptidase Complex isolation & purification
Abstract

The proteasome is a multicatalytic protease complex present in all eukaryotic cells, which plays a critical role in regulating essential cellular processes. During the immune response to pathogens, stimulation by γ interferon induces the production of a special form of proteasome, the immunoproteasome. Inappropriate increase of proteosomal activity has been linked to inflammatory and autoimmune diseases. Selective inhibition of the immunoproteasome specific LMP7 subunit was shown to block inflammatory cytokine secretion in human PBMC, thus making the immunoproteasome an interesting target to fight autoimmune diseases. This paper describes a method for purification and separation of the 20S immunoproteasomes from the constitutive proteasome, which is ubiquitously present in all cells, based on hydrophobic interaction chromatography. The purified immunoproteasome showed several bands, between 20-30 kDa, when subjected to polyacrylamide gel electrophoresis under denaturing conditions. The purified proteasome complexes had a molecular mass of approximately 700 kDa as estimated by gel filtration. Identification of the catalytic subunits in the immunoproteasomes was performed in Western blot with antibodies directed specifically against either the constitutive or the immunoproteasome subunits. The purified immunoproteasome possessed all three protease activities associated with the proteasome complex. LC/MS analysis confirmed the presence of the three immunoproteasome catalytic subunits in the purified immunoproteasome., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2013
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