title: Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.
abstract: Missense mutations (P56S) in Vapb are associated with autosomal dominant motor neuron diseases: amyotrophic lateral sclerosis and lower motor neuron disease. Although transgenic mice overexpressing the mutant vesicle-associated membrane protein-associated protein B (VAPB) protein with neuron-specific promoters have provided some insight into the toxic properties of the mutant proteins, their role in pathogenesis remains unclear. To identify pathological defects in animals expressing the P56S mutant VAPB protein at physiological levels in the appropriate tissues, we have generated Vapb knock-in mice replacing wild-type Vapb gene with P56S mutant Vapb gene and analyzed the resulting pathological phenotypes. Heterozygous P56S Vapb knock-in mice show mild age-dependent defects in motor behaviors as characteristic features of the disease. The homozygous P56S Vapb knock-in mice show more severe defects compared with heterozygous mice reflecting the dominant and dose-dependent effects of P56S mutation. Significantly, the knock-in mice demonstrate accumulation of P56S VAPB protein and ubiquitinated proteins in cytoplasmic inclusions, selectively in motor neurons. The mutant mice demonstrate induction of ER stress and autophagic response in motor neurons before obvious onset of behavioral defects, suggesting that these cellular biological defects might contribute to the initiation of the disease. The P56S Vapb knock-in mice could be a valuable tool to gain a better understanding of the mechanisms by which the disease arises.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Larroquette
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seto
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Perrine L
authors.initials: PL
authors.lastname: Gaub
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Brishna
authors.initials: B
authors.lastname: Kamal
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, Cypress, TX, USA and.
authors.forename: Deeann
authors.initials: D
authors.lastname: Wallis
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Larivière
authors.affiliation: Departement of Neurosciences, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Vallée
authors.affiliation: Departement of Neurosciences, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Robitaille
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4, hiroshi.tsuda@mcgill.ca.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuda
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism*; D020125:Mutation, Missense; D013312:Stress, Physiological; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C496748:VAPB protein, human; C529892:VAPB protein, mouse; D033921:Vesicular Transport Proteins