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

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.