title: Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Mutations in calcium-responsive transactivator (CREST) encoding gene have been recently linked to ALS. Similar to several proteins implicated in ALS, CREST contains a prion-like domain and was reported to be a component of paraspeckles.
  
  
  RESULTS
  We demonstrate that CREST is prone to aggregation and co-aggregates with FUS but not with other two ALS-linked proteins, TDP-43 and TAF15, in cultured cells. Aggregation of CREST affects paraspeckle integrity, probably by trapping other paraspeckle proteins within aggregates. Like several other ALS-associated proteins, CREST is recruited to induced stress granules. Neither of the CREST mutations described in ALS alters its subcellular localization, stress granule recruitment or detergent solubility; however Q388stop mutation results in elevated steady-state levels and more frequent nuclear aggregation of the protein. Both wild-type protein and its mutants negatively affect neurite network complexity of unstimulated cultured neurons when overexpressed, with Q388stop mutation being the most deleterious. When overexpressed in the fly eye, wild-type CREST or its mutants lead to severe retinal degeneration without obvious differences between the variants.
  
  
  CONCLUSIONS
  Our data indicate that CREST and certain other ALS-linked proteins share several features implicated in ALS pathogenesis, namely the ability to aggregate, be recruited to stress granules and alter paraspeckle integrity. A change in CREST levels in neurons which might occur under pathological conditions would have a profound negative effect on neuronal homeostasis.
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff, UK. kukharskym@gmail.com.|Institute of Physiologically Active Compounds Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka, 142432, Moscow Region, Russian Federation. kukharskym@gmail.com.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Kukharsky
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff, UK. annamariaq89@hotmail.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Quintiero
authors.affiliation: Department of Neuropathology, The University of Tokyo, Tokyo, Japan. yorkkuppi@gmail.com.
authors.forename: Taisei
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Neuropathology, The University of Tokyo, Tokyo, Japan. matsuk.k213@gmail.com.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsukawa
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff, UK. yoeny205@gmail.com.
authors.forename: Haiyan
authors.initials: H
authors.lastname: An
authors.affiliation: Department of Neuropathology, The University of Tokyo, Tokyo, Japan. tonchan@m.u-tokyo.ac.jp.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Neuropathology, The University of Tokyo, Tokyo, Japan. iwatsubo@m.u-tokyo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff, UK. buchmanvl@cardiff.ac.uk.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff, UK. shelkovnikovat@cardiff.ac.uk.|Institute of Physiologically Active Compounds Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka, 142432, Moscow Region, Russian Federation. shelkovnikovat@cardiff.ac.uk.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Shelkovnikova
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C502810:SS18L1 protein, human; D015534:Trans-Activators; D002118:Calcium