Journal
JOURNAL OF NEUROCHEMISTRY
Volume 114, Issue 3, Pages 795-809Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2010.06806.x
Keywords
adeno-associated virus; amyotrophic lateral sclerosis; calcium; endoplasmic reticulum stress; motoneuron culture; vesicle-associated membrane protein-associated protein B
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Funding
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- American ALS association (ALSA)
- Association Francaise contre les Myopathies (AFM)
- Conseil General des Bouches-du-Rhone
- Swiss National Science Foundation
- Agence Nationale de la Recherche (ANR)
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P>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 (Ca2+) 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 Ca2+ signals and ER-derived death pathways as important events in the motoneuron degenerative process.
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