Identification and functional dissection of localization signals within ataxin-3.
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.
Antony
Paul Michel Aloyse
PM
Medical Genetics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
Mäntele
Simone
S
Mollenkopf
Phillip
P
Boy
Jana
J
Kehlenbach
Ralph H
RH
Riess
Olaf
O
Schmidt
Thorsten
T
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
D009419:Nerve Tissue Proteins; D049790:Nuclear Export Signals; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3