Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome (Articolo in rivista)

Type
Label
  • Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome (Articolo in rivista) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1242/jcs.102137 (literal)
Alternative label
  • Giulia Papiani, Annamaria Ruggiano, Matteo Fossati, Andrea Raimondi, Giovanni Bertoni, Maura Francolini, Roberta Benfante, Francesca Navone, Nica Borgese (2012)
    Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome
    in Journal of cell science
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Giulia Papiani, Annamaria Ruggiano, Matteo Fossati, Andrea Raimondi, Giovanni Bertoni, Maura Francolini, Roberta Benfante, Francesca Navone, Nica Borgese (literal)
Pagina inizio
  • 3601 (literal)
Pagina fine
  • 3611 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 125 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Consiglio Nazionale delle Ricerche, Institute of Neuroscience and Department of Medical Biotechnology and Translational Medicine , University of Milan, Milano, Italy Department of Nanochemistry, The Italian Institute of Technology, Genova, Italy Department of Neuroscience and Brain Technology, The Italian Institute of Technology, Genova, Italy Department of Health Science, University of Catanzaro ''Magna Graecia'', Roccelletta di Borgia (CZ), Italy (literal)
Titolo
  • Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome (literal)
Abstract
  • VAPB (vesicle-associated membrane protein-associated protein B) is a ubiquitously expressed, ER-resident tail-anchored protein that functions as adaptor for lipid-exchange proteins. Its mutant form, P56S-VAPB, is linked to a dominantly inherited form of amyotrophic lateral sclerosis (ALS8). P56S-VAPB forms intracellular inclusions, whose role in ALS pathogenesis has not yet been elucidated. We recently demonstrated that these inclusions are formed by profoundly remodelled stacked ER cisternae. Here, we used stable HeLa-TetOff cell lines inducibly expressing wild-type VAPB and P56S-VAPB, as well as microinjection protocols in non-transfected cells, to investigate the dynamics of inclusion generation and degradation. Shortly after synthesis, the mutant protein forms small, polyubiquitinated clusters, which then congregate in the juxtanuclear region independently of the integrity of the microtubule cytoskeleton. The rate of degradation of the aggregated mutant is higher than that of the wild-type protein, so that the inclusions are cleared only a few hours after cessation of P56S-VAPB synthesis. At variance with other inclusion bodies linked to neurodegenerative diseases, clearance of P56S-VAPB inclusions involves the proteasome, with no apparent participation of macro-autophagy. Transfection of a dominant-negative form of the AAA ATPase p97/VCP stabilizes mutant VAPB, suggesting a role for this ATPase in extracting the aggregated protein from the inclusions. Our results demonstrate that the structures induced by P56S-VAPB stand apart from other inclusion bodies, both in the mechanism of their genesis and of their clearance from the cell, with possible implications for the pathogenic mechanism of the mutant protein. (literal)
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