While teaching the central dogma of biology, I have found that students grasp the processes of transcription (DNA to RNA) and translation (RNA to protein). However, I have observed that students often struggle to understand the concept of the next step in the process of producing a functional protein, which involves the folding of a translated linear strand of amino acids into a 3D structure. The complex challenge of correctly processing and folding a cellular protein is partially dictated by the amino acid sequence of that protein. Additionally, many cellular proteins assist in the folding process, and guide a folding protein toward its native conformation. Once folded, it is both the 3D structure and the cellular localization of the protein that allows it to function properly. In the case of protein-misfolding diseases, these folding processes can be altered by gene variations (inherited or acquired) or abnormal amino acid modifications. These alterations can influence the protein-folding process and potentially produce a nonfunctional or misfolded protein. To counteract protein misfolding, the cell contains a quality-control system that identifies nonfunctional or altered intracellular proteins, and ensures that the misfolded products are directed to proteasome – a large multisubunit protease – for degradation Citation[1], before they cause any harm. If not degraded, the escaped components of misfolded proteins can aggregate and cause cell toxicity or death.
Protein misfolding and improper processing by the cellular quality-control system causes many highly debilitating disorders, ranging from heritable disease, such as cystic fibrosis (CF) and a1-antitrypsin, to neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and prion diseases. Additional diseases, including diabetes and cancer, are also affected by misfolded proteins. Interestingly, proteins using the secretory pathway for folding and trafficking are known to constitute a disproportionate share of inherited misfolding diseases. Even though it is well understood that the linear arrangement of amino acids dictates protein function, the intermediate states of protein folding, processing and/or aggregation are not fully understood. The advancement of experimental tools is of great importance for examining the components of protein biogenesis. The advent of proteomics has made it possible to examine the proteins critical in protein-misfolding disorders. Furthermore, this technology offers great promise in the identification of molecules that bind to, and stabilize, native conformations of proteins, which may allow rescue from protein sorting by the quality-control system and retention of functional activity.
Proteomics is currently considered a key technology in the global analysis of cellular response by analyzing protein expression to understand gene functions Citation[2,3]. Owing to multiple changes in the cell at a given time, proteomics offers a powerful tool in the study of differential protein expression and post-translational modifications caused by drug treatment and disease-specific changes. These proteins may be diagnostic or therapeutic targets, and additionally have great potential to advance our understanding of the basic concepts of protein-misfolding diseases. This special issue of Expert Review of Proteomics highlights the unprecedented opportunities offered by ongoing proteomic-based research in protein-misfolding diseases, and aims to shed light on potential therapeutic targets for future drug development.
The articles in this special issue give an interdisciplinary insight into the proteomic approaches of protein-folding research, including the exploration of mechanisms of disease and therapeutic development. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The most common mutation is deletion of phenylalanine at position 508 (ΔF508), which results in a misfolded CFTR protein that is prematurely targeted for degradation. Henderson and colleagues provide a unique analysis of advancing therapeutics targeting the prevention of premature CFTR proteolysis. The authors have highlighted several proteomics-based investigations to identify the molecules that may be unlikely candidates but, nonetheless, of great importance in the regulation of CFTR processing. Further, Gomes-Alves and Penque uncover the key players in ΔF508 CFTR processing and trafficking. Towards the therapeutic intervention, Collawn and colleagues have discussed the role of small-molecule correctors (chemical chaperones) and compounds that may have the ability to correct two classes (I and II) of mutations in the treatment of CF.
Among protein misfolding-mediated disorders, Alzheimer’s, Parkinson and Huntington’s disease and amyotrophic lateral sclerosis are among the most highly investigated neurodegenerative syndromes worldwide. Santucci and colleagues describe a number of neurodegenerative diseases and discuss the mechanisms responsible at the molecular level. There are many important features of protein aggregation in neurodegenerative disorders that have been elucidated. Rodolfo and colleagues have presented unique proteomics-based features of mitochondrial dysfunction in neurodegenerative pathologies. Owing to different amino acid sequences and compositions, the intrinsically disordered proteins are often involved in the regulation, signaling and control mechanism of protein dysfunction maladies, including neurodegeneration. In an insightful article, Uversky details the role of intrinsically disordered proteins in neurodegeneration and defines the peculiarities of intrinsically disordered proteins as potential drug targets in neurodegenerative disorders. In a review focused on therapeutic interventions of neurodegenerative disorders, Robinson provides a well-defined understanding of the molecular basis of Parkinson’s disease, and reviews biomarkers that may provide potential routes of Parkinson’s disease therapy. Although most neurodegenerative disorders share a common mechanistic theme in the deposition of misfolded proteins, there is no effective treatment that can regress the disease progression. Ho and Pasinetti provide accumulating evidences regarding neutriceutical grape-seed polyphenolic extract, which could mitigate protein misfolding-mediated neuropathologic and clinical phenotypes.
Traditionally, protein misfolding has been linked to an array of heritable diseases and neurodegenerative disorders. Emerging evidence suggests that protein-misfolding diseases can also have a fundamental role in malignancy Citation[4,5]. Khan has have described the ‘seed’ and ‘soil’ of malignant growth, in particular, by discussing the fusion oncoprotein that interplays in the protein-misfolding pathway and unfolded-protein response. This protein is linked to acute promyelocytic leukemia by promoting the misfolding of nuclear receptor corepressor protein; a corepressor for the growth-suppressive function of several tumor-suppressor proteins. Focusing on therapeutic interventions, Nehme and Mus-Veteau describe the role of proteins involved in the Hedgehog signaling pathway, and the potential for effective and novel treatments of cancer. Furthermore, Nagaraj and colleagues discuss proteomics-based strategies to comprehend novel targets in protein misfolding and cancer therapy.
These reports elucidate several broad-ranging areas of protein-misfolding diseases. As a whole, these reports highlight the importance of proteomics-based identification of therapeutic targets. I hope readers will find these articles interesting and helpful to their research pursuits. It has been my pleasure to put together this special issue in Expert Review of Proteomics. I would like to thank the editorial staff at Future Science Group, for their great assistance and for providing a unique forum in which to review and report their ongoing research activities. I would also like to thank all of the contributing authors for sharing their quality research and ideas throughout this special issue.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
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- Ng APP, Nin DS, Fong JH, Venkataraman D, Chen C-S, Khan M. Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein. Mol. Cancer Ther.6, 2240–2248 (2007).
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