title: Senataxin, the yeast Sen1p orthologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease.
abstract: A severe recessive cerebellar ataxia, Ataxia-Oculomotor Apraxia 2 (AOA2) and a juvenile onset form of dominant amyotrophic lateral sclerosis (ALS4) result from mutations of the Senataxin (SETX) gene. To begin characterization this disease protein, we developed a specific antibody to the DNA/RNA helicase domain of SETX. In murine brain, SETX concentrates in several regions, including cerebellum, hippocampus and olfactory bulb with a general neuronal expression profile, colocalizing with NeuN. In cultured cells, we found that SETX was cytoplasmically diffuse, but in the nucleus, SETX was punctate, colocalizing with fibrillarin, a marker of the nucleolus. In differentiated non-cycling cells, nuclear SETX was not restricted to the nucleolus but was diffuse within the nucleoplasm, suggesting cell-cycle-dependent localization. SETX missense mutations cluster within the N-terminus and helicase domains. Flag tagging at the N-terminus caused protein mislocation to the nucleoplasm and failure to export to the cytoplasm, suggesting that the N-terminus may be essential for correct SETX localization. We report here the first characterization of SETX protein, which may provide future insights into a new mechanism leading to neuron death.
authors.affiliation: Department of Pediatrics, Division of Genetics and Developmental Medicine, University of Washington School of Medicine, Seattle, WA 63110, USA.
authors.forename: Ying-Zhang
authors.initials: YZ
authors.lastname: Chen
authors.forename: Sayed H
authors.initials: SH
authors.lastname: Hashemi
authors.forename: Susan K
authors.initials: SK
authors.lastname: Anderson
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Huang
authors.forename: Maria-Ceu
authors.initials: MC
authors.lastname: Moreira
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Chance
authors.forename: Craig L
authors.initials: CL
authors.lastname: Bennett
mesh_terms: D000328:Adult; D000818:Animals; D001259:Ataxia / Q000378:metabolism*; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D016472:Motor Neuron Disease / Q000378:metabolism*; D009154:Mutation; D020365:RNA Helicases / Q000502:physiology*
chemical_list: D020365:RNA Helicases