title: Identification and functional dissection of localization signals within ataxin-3.
abstract: Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) belongs to a group of autosomal dominant neurodegenerative diseases, which are caused by the expansion of a polyglutamine repeat in the affected protein, in this case ataxin-3. Ataxin-3 is mainly localized in the cytoplasm; however, one hallmark of SCA3 is the formation of ataxin-3-containing protein aggregates in the nucleus of neurons. Currently, it is not known how mutant ataxin-3 translocates into the nucleus. We performed localization assays of recently proposed and novel potential signals, functionally confirmed the activity of a nuclear localization signal, identified two novel nuclear export signals (NES 77 and NES 141), and determined crucial amino acids. In addition, we demonstrate the relevance of the identified signals for the intracellular localization of the N- and C-terminus of ataxin-3. Our findings stress the importance of investigating the mechanisms, which influence the intracellular distribution of ataxin-3 during the pathogenesis of SCA3.
authors: Medical Genetics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
authors: Paul Michel Aloyse
authors: PM
authors: Antony
authors: Simone
authors: S
authors: Mäntele
authors: Phillip
authors: P
authors: Mollenkopf
authors: Jana
authors: J
authors: Boy
authors: Ralph H
authors: RH
authors: Kehlenbach
authors: Olaf
authors: O
authors: Riess
authors: Thorsten
authors: T
authors: Schmidt
mesh_terms: D000595:Amino Acid Sequence; D000067699:Ataxin-3; D002467:Cell Nucleus / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D049790:Nuclear Export Signals / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D009419:Nerve Tissue Proteins; D049790:Nuclear Export Signals; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3