title: Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.
abstract: Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.
authors.affiliation: MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Tudor
authors.forename: C M
authors.initials: CM
authors.lastname: Galtrey
authors.forename: M S
authors.initials: MS
authors.lastname: Perkinton
authors.forename: K-F
authors.initials: KF
authors.lastname: Lau
authors.forename: K J
authors.initials: KJ
authors.lastname: De Vos
authors.forename: J C
authors.initials: JC
authors.lastname: Mitchell
authors.forename: S
authors.initials: S
authors.lastname: Ackerley
authors.forename: T
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: E
authors.initials: E
authors.lastname: Vámos
authors.forename: P N
authors.initials: PN
authors.lastname: Leigh
authors.forename: C
authors.initials: C
authors.lastname: Klasen
authors.forename: D M
authors.initials: DM
authors.lastname: McLoughlin
authors.forename: C E
authors.initials: CE
authors.lastname: Shaw
authors.forename: C C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D033921:Vesicular Transport Proteins
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C529892:VAPB protein, mouse; D033921:Vesicular Transport Proteins