title: Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies.
abstract: BACKGROUND
  A novel class of inherited human neurodegenerations is now known to be caused by expanded CAG repeats encoding polyglutamines. Polyglutamine-containing protein fragments have been shown to accumulate as aggregates in the nucleus and in the cytoplasm, and to induce cell death when expressed in cultured cells, leading to the proposal that polyglutamine aggregation is an important step in the pathogenesis. Supporting this, nuclear inclusions containing expanded polyglutamines have been identified in neurones from the brains of patients and in neurones from transgenic mouse models of this class of neural disorders.
  
  
  RESULTS
  We analysed the consequences of polyglutamine expression in PC12 neuronal cells. Activated SEK1 accumulated with nuclear but not cytoplasmic polyglutamine aggregations, which consequently triggers cell death. Cell death induced by polyglutamine expression was inhibited by a dominant-negative SEK1 (DN-SEK1), but not by DN-SEK1 tagged with a nuclear export signal. Steady state SEK1 expression itself was enhanced two to three-fold. Nuclearly aggregated polyglutamines, which were identified in PML bodies, co-localized with not only activated SEK1 but also activated c-Jun. We also observed that nuclear inclusion-positive neurones from brains with Huntington's disease expressed SEK1.
  
  
  CONCLUSIONS
  This study provides molecular links between the neurodegeneration observed in polyglutamine diseases, cell death signalling kinase cascades and nuclear subdomains related to cell death. We propose that the nuclear PML bodies containing polyglutamine aggregates activate the SEK1-JNK kinase cascade, resulting in the transduction of a death signal.
authors.affiliation: The fourth Department, Osaka Bioscience Institute, Osaka 565-0874; Graduate Course, Kyoto University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yasuda
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: H
authors.initials: H
authors.lastname: Higashiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Fuyuhiro
authors.forename: O
authors.initials: O
authors.lastname: Komure
authors.forename: F
authors.initials: F
authors.lastname: Tanaka
authors.forename: G
authors.initials: G
authors.lastname: Sobue
authors.forename: K
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: H
authors.initials: H
authors.lastname: Ichijo
authors.forename: A
authors.initials: A
authors.lastname: Kakizuka
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D048670:MAP Kinase Kinase 4; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D051381:Rats; D014162:Transfection; D018911:Trinucleotide Repeats; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D008164:Luminescent Proteins; D010455:Peptides; D014452:Ubiquitins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases