Identification of novel and disease related VCP binding partners and characterization of the skeletal muscle and cardiac pathology in a R155C-VCP knock-in mouse: a key to the understanding of human protein aggregate myopathies and cardiomyopathies

• Applicant: Professor Dr. Rolf Schröder
• Subject Area: Anatomy and Physiology
• Term: from 2007 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35021394

Mutations of the human valosin containing protein (VCP) gene on chromosom 9p13-p12 cause autosomal dominant IBMPFD, inclusion body myopathy (IBM) associated with Paget disease of the bone (P) and frontotemporal dementia (FD) or IBMPFD. Beyond the first description of a novel type of VCP-related frontotemporal dementia, we recently provided the first report on a novel form of VCP-related cardiomyopathy. We demonstrated that the IBMPFD striated muscle pathology is morphologically characterized by VCP- and ubiquitin-positive cytoplasmic and nuclear protein aggregates. The corroborative data on VCP-related IBMPFD currently indicates that the molecular pathogenesis of the disorder is related to an impairment of the ubiquitin proteasome protein degradation system. The major goals of our current project are the identification of novel and disease related VCP binding partners and the characterization of the skeletal muscle and cardiac pathology in a R155C-VCP knock-in mouse. Our project strives to provide new insights in the complex molecular mechanisms leading to abnormal protein aggregation and progressive muscle damage in IBMPFD and related forms of protein aggregate myopathies and cardiomyopathies.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Christoph S. Clemen