Koike, M., Fukushi, J., Ichinohe, Y., Higashimae, N., Fujishiro, M., Sasaki, C., Yamaguchi, M., Uchihara, T., Yagishita, S., Ohizumi, H., Hori, S., Kakizuka, A. (2010). Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression.  J. Biol. Chem. 285(28): 21736--21749.

FBrf0211185

Research paper

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.

PMC2898386 (PMC) (EuropePMC)