Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia

Abstract

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD. Although IBMPFD is a multisystem disorder, muscle weakness is the presenting symptom in greater than half of patients and an isolated symptom in 30%. Patients with the full spectrum of the disease make up only 12% of those affected; therefore it is important to consider and recognize IBMPFD in a neuromuscular clinic. The current review describes the skeletal muscle phenotype and common muscle histochemical features in IBMPFD. In addition to myopathic features; vacuolar changes and tubulofilamentous inclusions are found in a subset of patients. The most consistent findings are VCP, ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions. VCP is a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to protein degradation. Although the role of VCP in skeletal muscle is currently unknown, it is clear that VCP mutations lead to the accumulation of ubiquitinated inclusions and protein aggregates in patient tissue, transgenic animals and in vitro systems. We suggest that IBMPFD is novel type of protein surplus myopathy. Instead of accumulating a poorly degraded and aggregated mutant protein as seen in some myofibrillar and nemaline myopathies, VCP mutations disrupt its normal role in protein homeostasis resulting in the accumulation of ubiquitinated and aggregated proteins that are deleterious to skeletal muscle.

Figures

Figure 1

Histochemical and immunohistochemical stains of IBMPFD patient muscle biopsies. A) hematoxylin and eosin demonstrating large regions of grouped atrophy with smaller fibers containing rimmed vacuole, B) A fiber with a prominent rimmed vacuole seen with modified gomori trichrome stain, C) congo red staining demonstrating fibers with vacuoles and basophilic debris. D) Immunostaining with an anti-ubiquitin antibody (FK2) demonstrates large inclusions that are myonuclear and subsarcolemmal. E) A vacuolated fiber with VCP inclusions. F) TDP-43 immunostaining sarcoplasmic inclusions. Closed arrows highlight vacuoles and open arrows denote inclusions

Figure 2

A) Space fill diagram of a VCP hexamer (top) with each monomer colored individually and a linear diagram of a single VCP monomer showing the N-domain, L1 and L2 linkers, D1 and D2 ATPase domains and the C-terminal domain (bottom). Red space fill in hexamer represents residues that are mutated in IBMPFD. *Mutation T262A is unpublished (Spina S and Ghetti B, 2007 American Academy of Neurology Meeting).

Figure 3

Proposed functions of VCP. 1) VCP participates in the retrotranslocation and subsequent ubiquitination of ERAD substrates via binding to derlin-1 and one of several ER associated E3 ubiquitin ligases such as Hrd1 or gp78. 2) VCP shuttles ubiquitinated protein substrates to the 26S proteasome via interactions with rad23. 3) VCP mediates degradation of many short-lived signaling molecules such as Unc-45b and IκB. Unc-45 is responsible for myosin folding and myofibrillogenesis and IkB mediates NFkB signal transduction. 4) In the setting of UPS dysfunction or protein misfolding, VCP associates with small ubiquitinated protein aggregates and facilitates their sequestration into “aggresomes” via direct interactions with HDAC6. Aggresomes are then degraded via the autophagosome-lysosome system.