title: A mutation in VAPB that causes amyotrophic lateral sclerosis also causes a nuclear envelope defect.
abstract: A proline to serine mutation (P56S) in vesicle-associated membrane protein-associated protein B and C (VAPB) causes an autosomal dominant form of amyotrophic lateral sclerosis (ALS). We show that the mutation also causes a nuclear envelope defect. Transport of nucleoporins (Nups) and emerin (EMD) to the nuclear envelope is blocked, resulting in their sequestration in dilated cytoplasmic membranes. Simultaneous overexpression of the FFAT motif (two phenylalanine residues in an acidic track) antagonizes the effect of mutant VAPB and restores transport to the nuclear envelope. VAPB function is required for transport to the nuclear envelope, with knockdown of endogenous VAPB recapitulating this phenotype. Moreover, we identified the compartment into which the Nups and EMD were sequestered as the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), with nuclear envelope membrane proteins transiting to the ERGIC before VAPB-dependent retrograde transport to the nuclear envelope.
authors.affiliation: Neuroscience, Ottawa Hospital Research Institute, Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H 8M5,  Canada.
authors.forename: Duvinh
authors.initials: D
authors.lastname: Tran
authors.forename: Antonious
authors.initials: A
authors.lastname: Chalhoub
authors.forename: Allana
authors.initials: A
authors.lastname: Schooley
authors.forename: Wendy
authors.initials: W
authors.lastname: Zhang
authors.forename: Johnny K
authors.initials: JK
authors.lastname: Ngsee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; C092710:emerin