Journal
HUMAN MOLECULAR GENETICS
Volume 22, Issue 12, Pages 2350-2360Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt080
Keywords
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Funding
- Amyotrophic Lateral Sclerosis Association (ALSA) [1698]
- Agence Nationale de la Recherche (ANR JCJC Dynemit)
- Association pour la recherche sur la SLA et les autres maladies du motoneurone (ARSla)
- Thierry Latran Foundation
- Association Pour La Recherche Et le Developpement de Moyens de Lutte Contre les Maladies Neurodegeneratives (AREMANE)
- European Community [259867]
- Helmholtz Institute
- Canadian Institutes of Health Research (CIHR)
- Muscular Dystrophy Association USA
- Atip/Avenir Inserm award
- Robert Packard Foundation
- ARSla
- Marie Curie Actions
- AFM
- Mercator Professorship (DFG)
- contrat d'interface INSERM/AP-HP
- Canada Research Chairs
- ENP Graduate Programme fellowship of the Ecole des Neurosciences de Paris Ile-de-France
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The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function.
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