title: AAV-mediated expression of wild-type and ALS-linked mutant VAPB selectively triggers death of motoneurons through a Ca2+-dependent ER-associated pathway.
abstract: A dominant mutation in the gene coding for the vesicle-associated membrane protein-associated protein B (VAPB) was associated with amyotrophic lateral sclerosis, a fatal paralytic disorder characterized by the selective loss of motoneurons in the brain and spinal cord. Adeno-associated viral vectors that we show to transduce up to 90% of motoneurons in vitro were used to model VAPB-associated neurodegenerative process. We observed that Adeno-associated viral-mediated over-expression of both wild-type and mutated form of human VAPB selectively induces death of primary motoneurons, albeit with different kinetics. We provide evidence that ER stress and impaired homeostatic regulation of calcium (Ca(2+)) are implicated in the death process. Finally, we found that completion of the motoneuron death program triggered by the over-expression of wild-type and mutant VAPB implicates calpains, caspase 12 and 3. Our viral-based in vitro model, which recapitulates the selective vulnerability of motoneurons to the presence of mutant VAPB and also to VAPB gene dosage effect, identifies aberrant Ca(2+) signals and ER-derived death pathways as important events in the motoneuron degenerative process.
authors.affiliation: Inserm-Avenir team, The Mediterranean Institute of Neurobiology, Marseille, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Langou
authors.forename: Anice
authors.initials: A
authors.lastname: Moumen
authors.forename: Christophe
authors.initials: C
authors.lastname: Pellegrino
authors.forename: Julianne
authors.initials: J
authors.lastname: Aebischer
authors.forename: Igor
authors.initials: I
authors.lastname: Medina
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods; D033921:Vesicular Transport Proteins
chemical_list: D008565:Membrane Proteins; C529892:VAPB protein, mouse; D033921:Vesicular Transport Proteins