Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Hsiao Fang Wang, Yu Tzu Shih, Chiung Ya Chen, Hsu Wen Chao, Ming Jen Lee, Yi Ping Hsueh

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4820-4837
Number of pages18
JournalJournal of Clinical Investigation
Volume121
Issue number12
DOIs
Publication statusPublished - Dec 1 2011
Externally publishedYes

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Neurofibromin 1
Dendritic Spines
Frontotemporal Dementia
Osteitis Deformans
Muscular Diseases
Inclusion Bodies
Neurofibromatosis 1
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Neurofibromatosis 1 Genes
Mutation
Learning Disorders
CDC48 protein
Synapses
Dementia
Phenotype
Neurons
Bone and Bones

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. / Wang, Hsiao Fang; Shih, Yu Tzu; Chen, Chiung Ya; Chao, Hsu Wen; Lee, Ming Jen; Hsueh, Yi Ping.

In: Journal of Clinical Investigation, Vol. 121, No. 12, 01.12.2011, p. 4820-4837.

Research output: Contribution to journalArticle

Wang, Hsiao Fang ; Shih, Yu Tzu ; Chen, Chiung Ya ; Chao, Hsu Wen ; Lee, Ming Jen ; Hsueh, Yi Ping. / Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 12. pp. 4820-4837.
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