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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.

SUBMITTER: Koike M 

PROVIDER: S-EPMC2898386 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression.

Koike Masaaki M   Fukushi Junpei J   Ichinohe Yuzuru Y   Higashimae Naoki N   Fujishiro Masahiko M   Sasaki Chiyomi C   Yamaguchi Masahiro M   Uchihara Toshiki T   Yagishita Saburo S   Ohizumi Hiroshi H   Hori Seiji S   Kakizuka Akira A  

The Journal of biological chemistry 20100421 28


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 V  ...[more]

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