Proteotoxicity: an unappreciated mechanism of heart disease and its potential for novel therapeutics

European Coordinator:
  • Mathias GAUTEL, King's College, London (UK)
North American Coordinator:
  • Jeffrey ROBBINS, Cincinnati Children's Hospital (USA)
  • Lucie CARRIER, Hamburg University Medical Center (Germany)
  • Joseph HILL, University of Texas Southwestern Medical Center, Dallas (USA)
  • Marcus KRUGER, Max Planck Institute for Heart and Lung Research, Bad Nauheim (Germany)
  • Cam PATTERSON, New York-Presbyterian/Well Cornell Medical Center (USA)
  • Marco SANDRI, Venetian Institute of Molecular Medicine, Padova (Italy)
  • Monte WILLIS, University of North Carolina, Chapel Hill (USA)

Like skeletal muscle, cardiac muscle has the remarkable ability to adapt quickly to changes in workload and stimulation.  This adaptation is accomplished by changes in muscle cell contractility, electric behavior, metabolism, and growth.  More fundamentally, these changes result from alterations in gene expression, protein synthesis, and protein breakdown.  Indeed, maintaining an appropriate balance between protein formation and breakdown is important for the normal function and adaptation of cardiac muscle cells. Many inherited cardiac diseases are caused by mutations in cardiac muscle proteins, and many environmental stresses can lead to errors in protein formation.   In both cases, the abnormalities may adversely affect protein function and turnover.  It is now emerging that failure to break down or clear proteins can result in proteotoxicity, a potential factor leading to inherited and acquired cardiac muscle diseases.

The network aims to define how defects in the two major pathways of protein breakdown, (the autophagy-lysosomal pathway and the ubiquitin-proteasome system), can lead to the buildup in cardiac muscle cells of unneeded or misfolded proteins and, ultimately, heart failure.  Using mouse and rabbit models and human tissue samples, this network will determine the role of proteotoxicity in genetic and non-genetic forms of heart failure; dissect out the genetic and signaling networks that regulate the two protein breakdown pathways; and search for targeted therapies that reduce or block proteotoxicity in the hopes of developing new clinical treatments for heart failure.