VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease

Abstract

Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCPR155H/+ knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies.

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

“…Ultrastructural analyses in Vcp-deficient zebrafish muscles revealed severely impaired myofibrillar organization, dysmorphic mitochondria and numerous vesicular bodies. This is consistent with previous findings in muscle tissue from mice carrying the human mutations VCP R155H and VCP A232E which also display pronounced vacuolization, degenerated mitochondria and loss of myofilament organization [29,31]. VCP plays a key role in protein degradation via the UPS, and haploinsufficient mice display significantly elevated levels of poly-ubiquitinated proteins due to severely impaired proteasomal function [19].…”

“…Autosomal dominant mutations in the human VCP gene cause the multisystemic degenerative disease IBMPFD where disease symptoms usually manifest late in life [18]. Mice carrying the most frequent human VCP mutation, arginine to histidine at position 155 (R155H), develop normally but exhibit severe degenerative pathologies during adulthood [29–31]. Interestingly, nullizygous vcp mice are not viable and die at a peri-implantation stage, demonstrating that VCP is fundamentally important for embryogenesis in mice [32].…”

The Cdc48 Protein and Its Cofactor Vms1 Are Involved in Cdc13 Protein Degradation

“…p62, NBR1, Cdc48, and PLIC) have been implicated in bringing ubiquitylated substrates to the autophagy machinery in mammalian cells. Interestingly, mutations in human Cdc48 (also called VCP) that impair its function in autophagy lead to a degenerative disorder termed inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (20,21). It will be important to determine whether human Vms1 is involved in this disorder.…”

Emerging Roles for hnRNPs in post-transcriptional regulation: what can we learn from flies?

“…Moreover, Drosophila gave the opportunity to analyse several aspects of a wide spectrum of neurodegenerative diseases collectively named proteinopathies, characterized by both hnRNPs functions alteration and/or loss (Tsuji et al 2012;Neumann et al 2007;Neumann et al 2006). In particular, the multisystem proteinopathy (MSP) is a rare disease in which inclusion body myopathy (IBM) is associated with Paget's disease of the bone (PDB), fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Badadani et al 2010). MSP is characterized by a progressive degeneration of muscle, brain, motor neurons and bones accompanied by prominent TDP-43 protein pathology (Badadani et al 2010).…”

“…In particular, the multisystem proteinopathy (MSP) is a rare disease in which inclusion body myopathy (IBM) is associated with Paget's disease of the bone (PDB), fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Badadani et al 2010). MSP is characterized by a progressive degeneration of muscle, brain, motor neurons and bones accompanied by prominent TDP-43 protein pathology (Badadani et al 2010).…”