title: Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression.
abstract: Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies & Solution Oriented Research for Science and Technology, Kyoto 606-8501, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Koike
authors.forename: Junpei
authors.initials: J
authors.lastname: Fukushi
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Ichinohe
authors.forename: Naoki
authors.initials: N
authors.lastname: Higashimae
authors.forename: Masahiko
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Chiyomi
authors.initials: C
authors.lastname: Sasaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchihara
authors.forename: Saburo
authors.initials: S
authors.lastname: Yagishita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohizumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Hori
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka
mesh_terms: D021581:Active Transport, Cell Nucleus; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D004331:Drosophila melanogaster / Q000235:genetics; D005822:Genetic Vectors; D006657:Histones / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D010455:Peptides; C097188:polyglutamine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; C000614180:Vcp protein, rat
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