Document Detail

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density.
MedLine Citation:
PMID:  22105171     Owner:  NLM     Status:  MEDLINE    
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.
Hsiao-Fang Wang; Yu-Tzu Shih; Chiung-Ya Chen; Hsu-Wen Chao; Ming-Jen Lee; Yi-Ping Hsueh
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-11-21
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  121     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-02     Completed Date:  2012-01-31     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4820-37     Citation Subset:  AIM; IM    
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
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MeSH Terms
Adenosine Triphosphatases / physiology*
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
Learning Disorders / drug therapy,  genetics
Lovastatin / pharmacology,  therapeutic use
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
Synapses / ultrastructure
Reg. No./Substance:
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
Comment In:
J Clin Invest. 2011 Dec;121(12):4627-30   [PMID:  22105166 ]

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