Abstract 548: Evolutionarily Conserved Functions for Valosin Containing Protein (VCP) in Cardiac and Skeletal Muscle Reveal Mechanistic Insights into Multisystem Proteinopathy

Abstract

Valosin Containing Protein (VCP)/p97 is a AAA-ATPase with functions in vast cellular protein quality control processes, including targeting of misfolded or aggregated proteins for degradation by the ubiquitin proteasome system and autophagy. Mutations in VCP cause a multisystem degenerative proteinopathy disorder that includes pathologies of the nervous system, skeletal muscle, bone, and heart. However, the molecular function of VCP in myocytes is unknown. We generated cardiomyocyte-specific transgenic mice overexpressing wildtype VCP or a VCP K524A mutant with deficient ATPase activity. Mice overexpressing wildtype VCP exhibit normal cardiac structure and function while mutant VCP overexpressing mice develop cardiomyopathy and have elevated levels of ubiquitinated proteins in the heart. Additionally, we generated transgenic flies overexpressing wildtype VCP or VCP K524A in muscle. Flies overexpressing the VCP ATPase-deficient mutant have reduced flight ability at two days of age and are unable to fly at seven days of age, suggesting conserved indispensable homeostatic functions for VCP in heart and skeletal muscle. Moreover, mouse hearts and Drosophila indirect flight muscle overexpressing the ATPase-deficient VCP mutant exhibit profound ultrastructural abnormalities consistent with dysregulation of proteostasis. Extensive proteomics in Drosophila and in mouse heart identified conserved interactions of VCP with protein complexes that suggest unique functions for VCP in regulating novel quality control pathways in muscle. These data and novel regulatory relationships will be presented, which implicate important and evolutionarily conserved functions for VCP and suggest molecular mechanisms that underlie the molecular etiology of multisystem proteinopathy disorders.