| Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. | |
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MedLine Citation:
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PMID: 22105171 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1(+/-) mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation. |
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Authors:
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Hsiao-Fang Wang; Yu-Tzu Shih; Chiung-Ya Chen; Hsu-Wen Chao; Ming-Jen Lee; Yi-Ping Hsueh |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-11-21 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 121 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-02 Completed Date: 2012-01-31 Revised Date: 2013-05-23 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 4820-37 Citation Subset: AIM; IM |
Affiliation:
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Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphatases
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physiology* Animals CA1 Region, Hippocampal / ultrastructure Cell Cycle Proteins / physiology* Cells, Cultured / drug effects, ultrastructure Cholesterol / physiology Contracture / congenital*, genetics, pathology Dendrites / metabolism, ultrastructure* Frontotemporal Dementia / genetics*, pathology Humans Learning Disorders / drug therapy, genetics Lovastatin / pharmacology, therapeutic use Mice Mice, Knockout Mutation, Missense Myositis, Inclusion Body / congenital*, genetics, pathology Neurofibromatosis 1 / genetics*, pathology, psychology Neurofibromin 1 / deficiency, genetics, physiology* Ophthalmoplegia / genetics*, pathology Osteitis Deformans / genetics*, pathology Point Mutation Protein Interaction Mapping Protein Structure, Tertiary Pyramidal Cells / drug effects, ultrastructure Rats Synapses / ultrastructure |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Neurofibromin 1; 57-88-5/Cholesterol; 75330-75-5/Lovastatin; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/CDC48 protein |
| Comments/Corrections | |
Comment In:
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J Clin Invest. 2011 Dec;121(12):4627-30
[PMID:
22105166
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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