Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression.
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| 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.
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| Authors | Masaaki Koike, Junpei Fukushi, Yuzuru Ichinohe, Naoki Higashimae, Masahiko Fujishiro, Chiyomi Sasaki, Masahiro Yamaguchi, Toshiki Uchihara, Saburo Yagishita, Hiroshi Ohizumi, Seiji Hori, Akira Kakizuka |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 28 Pg. 21736-49 (Jul 09 2010) ISSN: 1083-351X [Electronic] United States |
| PMID | 20410307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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