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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Authors | Atsushi Manno, Masakatsu Noguchi, Junpei Fukushi, Yasuhiro Motohashi, Akira Kakizuka |
Journal | Genes to cells : devoted to molecular & cellular mechanisms
(Genes Cells)
Vol. 15
Issue 8
Pg. 911-22
(Aug 2010)
ISSN: 1365-2443 [Electronic] England |
PMID | 20604808
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cell Cycle Proteins
- Adenosine Triphosphatases
- VCP protein, human
- Valosin Containing Protein
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Topics |
- Adenosine Triphosphatases
(genetics, metabolism)
- Animals
- Cell Cycle Proteins
(genetics, metabolism)
- Cell Line
- Drosophila
- Frontotemporal Dementia
(complications, genetics, metabolism, pathology)
- Humans
- Inclusion Bodies
(genetics, metabolism, pathology)
- Muscular Diseases
(complications, genetics, metabolism, pathology)
- Mutation
- Osteitis Deformans
(complications, genetics, metabolism, pathology)
- Valosin Containing Protein
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