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Manno, A., Noguchi, M., Fukushi, J., Motohashi, Y., Kakizuka, A. (2010). Enhanced ATPase activities as a primary defect of mutant valosin-containing proteins that cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.  Genes Cells 15(8): 911--922.
FlyBase ID
FBrf0211278
Publication Type
Research paper
Abstract

Valosin-containing protein (VCP) has been shown to colocalize with abnormal protein aggregates, such as nuclear inclusions of Huntington disease and Machado-Joseph disease, Lewy bodies in Parkinson disease. Several mis-sense mutations in the human VCP gene have been identified in patients suffering inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). Recently, we have shown that VCP possesses both aggregate-forming and aggregate-clearing activities. Here, we showed that in cells treated with proteasome inhibitors VCP first appeared as several small aggregates throughout the cells; and then, these small aggregates gathered together into a single big aggregate. Subcellular localization and ATPase activity of VCP clearly influenced the localization of the aggregates. Furthermore, all tested IBMPFD-causing mutant VCPs, possessed elevated ATPase activities and enhanced aggregate-forming activities in cultured cells. In Drosophila, these mutants and VCP(T761E), a super active VCP, did not appear to spontaneously induce eye degeneration, but worsened the phenotype when co-expressed with polyglutamines. Unexpectedly, these VCPs did not apparently change sizes and the amounts of polyglutamine aggregates in Drosophila eyes. Elevated ATPase activities, thus, may be a hidden primary defect causing IBMPFD pathological phenotypes, which would be revealed when abnormal proteins are accumulated, as typically observed in aging.

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Genes Cells
    Title
    Genes to cells : devoted to molecular & cellular mechanisms
    Publication Year
    1996-
    ISBN/ISSN
    1356-9597
    Data From Reference
    Alleles (7)
    Genes (3)
    Human Disease Models (1)
    Natural transposons (1)
    Experimental Tools (1)
    Transgenic Constructs (7)