Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

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. W...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-07, Vol.285 (28), p.21736-21749
Main Authors: Koike, Masaaki, Fukushi, Junpei, Ichinohe, Yuzuru, Higashimae, Naoki, Fujishiro, Masahiko, Sasaki, Chiyomi, Yamaguchi, Masahiro, Uchihara, Toshiki, Yagishita, Saburo, Ohizumi, Hiroshi, Hori, Seiji, Kakizuka, Akira
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Adenosine Triphosphatases - chemistry
Adenosine Triphosphatases - physiology
Animals
ATPases
Atrophy
Cell Biology
Cell Cycle Proteins - chemistry
Cell Cycle Proteins - physiology
Cell Line
Drosophila
Drosophila melanogaster - genetics
Genetic Vectors
Histone Modification
Histones - chemistry
Humans
Mice
Mice, Transgenic
Molecular Bases of Disease
Neurodegeneration
Neurodegenerative Diseases - metabolism
Neurons - metabolism
NIH 3T3 Cells
PC12 Cells
Peptides - genetics
Peptides - metabolism
Polyglutamine
Protein Folding
Rats
Transcription
Transcription, Genetic
Valosin Containing Protein
VCP
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.099283