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J Neurochem. 2010 Aug;114(3):795-809. doi: 10.1111/j.1471-4159.2010.06806.x. Epub 2010 May 8.

AAV-mediated expression of wild-type and ALS-linked mutant VAPB selectively triggers death of motoneurons through a Ca2+-dependent ER-associated pathway.

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1
Inserm-Avenir team, The Mediterranean Institute of Neurobiology, Marseille, France.

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.

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