title: Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles PerturbsDrosophilaHeart Structure and Impairs Function.
abstract: Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP's role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in theDrosophilaheart. Cardiac-restricted RNAi-mediated knockdown of TER94, theDrosophilaVCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts.Drosophilamay therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology.
authors: Division of Cardiology, Department of Medicine, Johns Hopkins University, Ross 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors: Meera C
authors: MC
authors: Viswanathan
authors: Division of Cardiology, Department of Medicine, Johns Hopkins University, Ross 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors: Anna C
authors: AC
authors: Blice-Baum
authors: Institute of Biotechnology & Department of Life Science, National Tsing Hua University, Hsinchu City 30013, Taiwan.
authors: Tzu-Kang
authors: TK
authors: Sang
authors: Division of Cardiology, Department of Medicine, Johns Hopkins University, Ross 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University, Ross 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors: Anthony
authors: A
authors: Cammarato
keywords: IBMPFD; TER94; cdc48; multisystem proteinopathy; myopathy; p97