Protein post-translational modifications and misfolding: New concepts in heart failure

Authors

  • Federica del Monte,

    1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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  • Giulio Agnetti

    Corresponding author
    1. Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA
    2. DIBINEM, University of Bologna, Bologna, Italy
    • Correspondence: Dr. Giulio Agnetti, Johns Hopkins University, Bayview Campus, 5200 Eastern Avenue, Center Tower, Mason F. Lord Building, Room 609, Baltimore, MD 21224, USA; DIBINEM, Via Irnerio, 48 – 41026 Bologna, Italy

      E-mail: gagnett1@jhu.edu; giulio.agnetti@unibo.it

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Abstract

A new concept in the field of heart-failure (HF) research points to a role of misfolded proteins, forming preamyloid oligomers (PAOs), in cardiac toxicity. This is largely based on few studies reporting the presence of PAOs, similar to those observed in neurodegenerative diseases, in experimental and human HF. As the majority of proteinopathies are sporadic in nature, protein post-translational modifications (PTMs) likely play a major role in this growing class of diseases. In fact, PTMs are known regulators of protein folding and of the formation of amyloid species in well-established proteinopathies. Proteomics has been instrumental in identifying both chemical and enzymatic PTMs, with a potential impact on protein mis-/folding. Here we provide the basics on how proteins fold along with a few examples of PTMs known to modulate protein misfolding and aggregation, with particular focus on the heart. Due to its innovative content and the growing awareness of the toxicity of misfolded proteins, an “Alzheimer's theory of HF” is timely. Moreover, the continuous innovations in proteomic technologies will help pinpoint PTMs that could contribute to the process. This nuptial between biology and technology could greatly assist in identifying biomarkers with increased specificity as well as more effective therapies.

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