title: Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis.
abstract: 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 S160Δ). 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.
authors: Centre de Recherche de l’Institut du Cerveau et de la Moelle Épiniere (CRICM), Paris, France.
authors: Edor
authors: E
authors: Kabashi
authors: Hajer
authors: H
authors: El Oussini
authors: Valérie
authors: V
authors: Bercier
authors: François
authors: F
authors: Gros-Louis
authors: Paul N
authors: PN
authors: Valdmanis
authors: Jonathan
authors: J
authors: McDearmid
authors: Inge A
authors: IA
authors: Mejier
authors: Patrick A
authors: PA
authors: Dion
authors: Nicolas
authors: N
authors: Dupre
authors: David
authors: D
authors: Hollinger
authors: Jérome
authors: J
authors: Sinniger
authors: Sylvie
authors: S
authors: Dirrig-Grosch
authors: William
authors: W
authors: Camu
authors: Vincent
authors: V
authors: Meininger
authors: Jean-Philippe
authors: JP
authors: Loeffler
authors: Frédérique
authors: F
authors: René
authors: Pierre
authors: P
authors: Drapeau
authors: Guy A
authors: GA
authors: Rouleau
authors: Luc
authors: L
authors: Dupuis
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016415:Sequence Alignment; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D008565:Membrane Proteins; C496748:VAPB protein, human; C529892:VAPB protein, mouse; D033921:Vesicular Transport Proteins