Global gene expression profiling in R155H knock-in murine model of VCP disease.

Angèle Nalbandian,Virginia E Kimonis,Zuyi Wang,Susan Knoblach,Svetlana Ghimbovschi,Jouni Vesa,Eric P Hoffman,Katrina J Llewellyn

doi:10.1111/cts.12241

Abstract

Dominant mutations in the valosin-containing protein (VCP) gene cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, which is characterized by progressive muscle weakness, dysfunction in bone remodeling, and frontotemporal dementia. More recently, VCP has been linked to 2% of familial amyotrophic lateral sclerosis cases. VCP plays a significant role in a plethora of cellular functions including membrane fusion, transcription activation, nuclear envelope reconstruction, postmitotic organelle reassembly, and cell cycle control. To elucidate the pathological mechanisms underlying the VCP disease progression, we have previously generated a VCP(R155H/+) mouse model with the R155H mutation. Histological analyses of mutant muscle showed vacuolization of myofibrils, centrally located nuclei, and disorganized muscle fibers. Global expression profiling of VCP(R155H/+) mice using gene annotations by DAVID identified key dysregulated signaling pathways including genes involved in the physiological system development and function, diseases and disorders, and molecular and cellular functions. There were a total of 212 significantly dysregulated genes, several of which are involved in the regulation of proteasomal function and NF-κB signaling cascade. Findings of the gene expression study were validated by using quantitative reverse transcriptase polymerase chain reaction analyses to test genes involved in various signaling cascades. This investigation reveals the importance of the VCP(R155H/+) mouse model in the understanding of cellular and molecular mechanisms causing VCP-associated neurodegenerative diseases and in the discovery of novel therapeutic advancements and strategies for patients suffering with these debilitating disorders.

Highlights

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) is characterized by progressive muscle weakness, bone deformities, and premature dementia.[1]
The diagnosis of IBMPFD muscle disease is based on clinical findings including elevated serum creatinine kinase (CK) concentration myopathic electromyograms and skeletal muscle histology findings of rimmed vacuoles and inclusion bodies, which stain positive for ubiquitin and TAR DNA-binding protein-43 (TDP43) antibodies.[1,4,5,6]
valosin-containing protein (VCP) is involved in a number of cellular functions, most of which are related to ubiquitin-proteasome-dependent proteolysis of proteins that is mediated by Verification of dysregulated genes interaction with ubiquitinated polypeptide substrates.[21,34,35,36,37]

Summary

Introduction

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) is characterized by progressive muscle weakness, bone deformities, and premature dementia.[1]. The diagnosis of IBMPFD muscle disease is based on clinical findings including elevated serum creatinine kinase (CK) concentration myopathic electromyograms and skeletal muscle histology findings of rimmed vacuoles and inclusion bodies, which stain positive for ubiquitin and TAR DNA-binding protein-43 (TDP43) antibodies.[1,4,5,6]. Early-onset PDB is observed in 49% of IBMPFD patients.[1,3] It typically begins in the 30s to 40s, at a mean age of onset of 42 years. PDB is caused by excessive osteoclastic activity and susceptibility to deformities like bowing and fractures. It involves focal areas of increased bone turnover that typically leads to spine and/or hip pain and deformity of the long bones causing pathological fractures on occasion. The diagnosis of PDB is based on elevated concentrations of serum alkaline phosphatase, urine pyridinoline, and deoxypyridinoline, as well as on skeletal radiographs or radionuclide scans.[7,8]

Methods

Results

Conclusion