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

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.

Keywords: Heart failure; Post-translational modifications; Pre-amyloid oligomers.

Figure 1. Mechanisms of formation of amyloid species

Role of PTMs (chemical and enzymatic), at different stages of amyloid formation. Proteolytic cleavage is a common PTM in many examples of protein misfolding. The resulting “seed” starts a nucleation process which leads to the formation of intermediate pre-amyloid oligomers and fibrils. These grow into large aggregates which are commonly referred to as amyloid. A recent acquisition in the field is that PAOs are the toxic species whereas larger aggregates could represent a by-product of cell detoxification.