title: Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a motor neuron degenerative disease characterized by a progressive, and ultimately fatal, muscle paralysis. The human VAMP-Associated Protein B (hVAPB) is the causative gene of ALS type 8. Previous studies have shown that a loss-of-function mechanism is responsible for VAPB-induced ALS. Recently, a novel mutation in hVAPB (V234I) has been identified but its pathogenic potential has not been assessed. We found that neuronal expression of the V234I mutant allele in Drosophila (DVAP-V260I) induces defects in synaptic structure and microtubule architecture that are opposite to those associated with DVAP mutants and transgenic expression of other ALS-linked alleles. Expression of DVAP-V260I also induces aggregate formation, reduced viability, wing postural defects, abnormal locomotion behavior, nuclear abnormalities, neurodegeneration and upregulation of the heat-shock-mediated stress response. Similar, albeit milder, phenotypes are associated with the overexpression of the wild-type protein. These data show that overexpressing the wild-type DVAP is sufficient to induce the disease and that DVAP-V260I is a pathogenic allele with increased wild-type activity. We propose that a combination of gain- and loss-of-function mechanisms is responsible for VAPB-induced ALS.
authors: Centre for Integrative Physiology, Euan MacDonald Centre for Motor Neuron Disease Research, School of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors: Mario
authors: M
authors: Sanhueza
authors: Luigi
authors: L
authors: Zechini
authors: Trudy
authors: T
authors: Gillespie
authors: Giuseppa
authors: G
authors: Pennetta
keywords: ALS; Drosophila; Genetics; Neurodegeneration; VAPB