Abstract
From unicellular organisms to humans, cells have evolved elegant systems to facilitate careful folding of proteins and the maintenance of protein homeostasis. Key modulators of protein homeostasis include a large, conserved family of proteins known as molecular chaperones, which augment the folding of nascent polypeptides and temper adverse consequences of cellular stress. However, errors in protein folding can still occur, resulting in the accumulation of misfolded proteins that strain cellular quality-control systems. In some cases, misfolded proteins can be targeted for degradation by the proteasome or via autophagy. Nevertheless, protein misfolding is a feature of many complex, genetically and clinically pleiotropic diseases, including neurodegenerative disorders and cancer. In recent years, substantial progress has been made in unraveling the complexity of protein folding using model systems, and we are now closer to being able to diagnose and treat the growing number of protein-folding diseases. To showcase some of these important recent advances, and also to inspire discussion on approaches to tackle unanswered questions, Disease Models & Mechanisms (DMM) presents a special collection of reviews from researchers at the cutting-edge of the field.
Highlights
Launching the Disease Models & Mechanisms (DMM) Protein-Folding Disease series The completion of the human genome sequencing project in 2003 provided the research community with a wealth of information on gene organization and genetic regulatory sites, enhancing our understanding of the evolutionary history of our genomes, the varied processes that constitute human metabolism, and the relationship between gene function and specific diseases
The identification of a locus that is mutated in a specific disease, or of a base that is altered in an open reading frame, serves only as a starting point to uncover why a disease arises
In light of our growing understanding of the human genome and the emergence of new and improved methods in biochemistry and biophysics, the time is ripe to define how an aberrant conformation leads to disease, and how disease presentation is – in turn – modified by changes in protein homeostasis, or ‘proteostasis’ (Balch et al, 2008)
Summary
Launching the DMM Protein-Folding Disease series The completion of the human genome sequencing project in 2003 provided the research community with a wealth of information on gene organization and genetic regulatory sites, enhancing our understanding of the evolutionary history of our genomes, the varied processes that constitute human metabolism, and the relationship between gene function and specific diseases. One must understand how the mutation affects the function, or even the folding, of a specific protein. We start with a poster article from Julie Valastyan and Susan Lindquist that provides a general overview of the classes and causes of diseases that arise from protein misfolding (Valastyan and Lindquist, 2014).
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