Author(s): Langou K, Moumen A, Pellegrino C, Aebischer J, Medina I,
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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.
This article was published in J Neurochem
and referenced in Translational Medicine