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Another VCP interactor: NF is enough
Conrad C. Weihl
Conrad C. Weihl
Published November 21, 2011
Citation Information: J Clin Invest. 2011;121(12):4627-4630. https://doi.org/10.1172/JCI61126.
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Another VCP interactor: NF is enough

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Abstract

Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin-1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF1 may explain the dementia phenotype and cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1.

Authors

Conrad C. Weihl

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Figure 1

Function and dysfunction of VCP in health and disease.

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Function and dysfunction of VCP in health and disease.
(A) VCP is necess...
(A) VCP is necessary to maintain protein homeostasis in cells. In addition, via its association with tissue-specific substrates, VCP mediates specialized cellular processes such as synaptogenesis in neurons and myofibrillogenesis and caveolin-3 signaling in skeletal muscle. (B) IBMPFD-associated mutations in VCP disrupt protein homeostasis in VCP mutant–expressing cells, resulting in ubiquitinated inclusions, protein aggregates, and vacuolation. IBMPFD-associated VCP mutants also impair tissue-specific functions by failing to interact or regulate select substrates. This may explain the tissue-specific vulnerability in IBMPFD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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