Another VCP interactor: NF is enough

Weihl, Conrad C.

doi:10.1172/jci61126

Cited by 7 publications

(16 citation statements)

References 24 publications

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“…Similar to NF1, IBMPFD is also fully penetrant, but expressivity is variable, suggesting the involvement of genetic modifiers in the influence of phenotype [43,44]. Around 80-90% and 50% of patients develop inclusion body myopathy and osteolytic lesions, respectively, with a mean age of 42 years.…”

Section: Reviewmentioning

confidence: 99%

From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation

Hsueh

2012

J Biomed Sci

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Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct protein interaction between neurofibromin, the protein product of the NF1 gene, and VCP/p97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/p97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/p97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/p97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases.

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Section: Reviewmentioning

confidence: 99%

From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation

Hsueh

2012

J Biomed Sci

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“…VCP is the most intensely investigated member of the AAA protein family, which can be attributed to its diverse biological roles. This diversity results from the enzyme’s promiscuity in substrate and cofactor binding [ 3 , 4 ]. It helps maintain proteostasis in all cells, in part, by governing critical steps during ubiquitin-proteasome system-mediated protein degradation and ER-associated degradation [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…It helps maintain proteostasis in all cells, in part, by governing critical steps during ubiquitin-proteasome system-mediated protein degradation and ER-associated degradation [ 5 ]. Other biological processes that involve VCP include membrane fusion, transcriptional activation, apoptosis, protein folding, and protein aggregation clearance [ 1 , 3 , 4 , 6 ]. VCP also performs specialized functions in distinct tissues.…”

Section: Introductionmentioning

confidence: 99%

“…VCP also performs specialized functions in distinct tissues. In skeletal muscle, for example, it is essential for myofibrillogenesis [ 3 ]. Critical roles during muscle atrophy and in the accelerated degradation of muscle proteins have also been recently identified [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Autosomal dominant mutations in VCP cause a debilitating form of inclusion body myopathy formerly known as inclusion body myopathy associated with Paget’s disease of the bone and fronto-temporal dementia (IBMPFD) [ 9 ], which more recently has been designated “multisystem proteinopathy” (MSP) [ 10 ]. MSP is an inherited degenerative disorder characterized by highly heterogeneous and variably penetrant phenotypes [ 3 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. To date, more than 30 VCP missense mutations have been shown to cause MSP [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Drosophila Heart Structure and Impairs Function

Viswanathan

Blice-Baum

Sang

et al. 2016

JCDD

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Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP's role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology.

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Create and preserve: Proteostasis in development and aging is governed by Cdc48/p97/VCP

Franz

Ackermann

Hoppe

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The AAA-ATPase Cdc48 (also called p97 or VCP) acts as a key regulator in proteolytic pathways, coordinating recruitment and targeting of substrate proteins to the 26S proteasome or lysosomal degradation. However, in contrast to the well-known function in ubiquitin-dependent cellular processes, the physiological relevance of Cdc48 in organismic development and maintenance of protein homeostasis is less understood. Therefore, studies on multicellular model organisms help to decipher how Cdc48-dependent proteolysis is regulated in time and space to meet developmental requirements. Given the importance of developmental regulation and tissue maintenance, defects in Cdc48 activity have been linked to several human pathologies including protein aggregation diseases. Thus, addressing the underlying disease mechanisms not only contributes to our understanding on the organism-wide function of Cdc48 but also facilitates the design of specific medical therapies. In this review, we will portray the role of Cdc48 in the context of multicellular organisms, pointing out its importance for developmental processes, tissue surveillance, and disease prevention. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

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Another VCP interactor: NF is enough

Cited by 7 publications

References 24 publications

From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation

From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation

Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Drosophila Heart Structure and Impairs Function

Create and preserve: Proteostasis in development and aging is governed by Cdc48/p97/VCP

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