An increasingly aging population will add to the number of individuals suffering from amyloid. Protein Misfolding Diseases provides a systematic overview of the current and emerging therapies for these types of protein misfolding diseases, including Alzheimer's, Parkinson's, and Mad Cow. The book emphasizes therapeutics in an amyloid disease context to help students, faculty, scientific researchers, and doctors working with protein misfolding diseases bridge the gap between basic science and pharmaceutical applications to protein misfolding disease.
The role of metal ions in protein folding and structure is a critical topic to a range of scientists in numerous fields, particularly those working in structural biology and bioinorganic chemistry, those studying protein folding and disease, and those involved in the molecular and cellular aspects of metals in biological systems. Protein Folding an
Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.
For decades it has been known that structured conformations are important for the proper functioning of most cellular proteins. However, appreciation that protein folding to the functional conformations as well as the structural maintenance of protein molecules are very complex processes has only emerged during the last ten years. The intimate interplay uncovered by this scientific development led us to realize that perturbations of the protein folding process and disturbances of conformational maintenance are major disease mechanisms. This development has given rise to the concept of conformational diseases and the broader signature of protein folding diseases, comprising diseases in which mutations or environmental stresses may result in a partial misfolding that leads then to alternative conformations capable of disturbing cellular processes. This may happen by self-association (aggregation), as in prion and Alzheimer’s diseases, or by incorporation of alternatively folded subunits into structural entities, as in collagen diseases. Another possibility is that folding to the native structure is impaired or abolished, resulting in decreased stea- state levels of the correctly folded protein, as is observed in cystic fibrosis and 1-antitrypsin deficiency, as well as in many enzyme deficiencies. In addition, deficiencies of proteins that are engaged in assisting and supervising protein folding (protein quality control) may impair the folding of many other proteins, resulting in pathological phenotypes. Examples of this are the spastic paraplegia attributable to mutations in mitochondrial protease/chaperone complexes.
Aimed at "drug discoverers" – i.e. any scientist who is interested in neurodegenerative diseases in general, and in finding disease-modifying treatments in particular – the first edition of Molecular Targets in Protein Misfolding and Neurodegenerative Disease will contain both a detailed, discipline-specific coverage (paragraphs on medicinal chemistry, on clinical and preclinical characterization of compounds in development, on target identification and validation, on genetic factors influencing a pathology, etc.) and a drug discovery-oriented, overall evaluation of each target (validation, druggability, existing leads, etc.). Together these will satisfy the needs of various audiences, including in vitro biologists, pharmacologists, medicinal chemists, etc. - Written to provide a comprehensive coverage of disease-modifying mechanisms and compounds against neurodegenerative diseases - Provides a "drug discovery application oriented perspective, evaluating targets and candidates for their overall therapeutic potential - Provides discipline-specific chapters (medicinal chemistry, target validation, preclinical and clinical development - Provides an overview on a number of molecular mechanisms (e.g. phosphorylation, chaperon refolding, ubiquitination, autophagy, microtubule transportation, protease cleavage, etc.) with relevance for any disease area - Contains a more thorough description of the therapeutic relevance of ~10 specific molecular targets
Molecular chaperones are involved in a wide variety of essential cellular processes in living cells. A subset of molecular chaperones have been initially described as heat shock proteins protecting cells from stress damage by keeping cellular proteins in a folding competent state and preventing them from irreversible aggregation. Later it became obvious that molecular chaperones are also expressed constitutively in the cell and are involved in complex processes such as protein synthesis, intracellular protein transport, post-translational modification and secretion of proteins as well as receptor signalling. Hence, it is not surprising that molecular chaperones are implicated in the pathogenesis of many relevant diseases and could be regarded as potential pharmacological targets. Starting with the analysis of the mode of action of chaperones at the molecular, cellular and organismic level, this book will then describe specific aspects where modulation of chaperone action could be of pharmacological and therapeutic interest.
Bio-Nanoimaging: Protein Misfolding & Aggregation provides a unique introduction to both novel and established nanoimaging techniques for visualization and characterization of misfolded and aggregated protein species. The book is divided into three sections covering: - Nanotechnology and nanoimaging technology, including cryoelectron microscopy of beta(2)-microglobulin, studying amyloidogensis by FRET; and scanning tunneling microscopy of protein deposits - Polymorphisms of protein misfolded and aggregated species, including fibrillar polymorphism, amyloid-like protofibrils, and insulin oligomers - Polymorphisms of misfolding and aggregation processes, including multiple pathways of lysozyme aggregation, misfolded intermediate of a PDZ domain, and micelle formation by human islet amyloid polypeptide Protein misfolding and aggregation is a fast-growing frontier in molecular medicine and protein chemistry. Related disorders include cataracts, arthritis, cystic fibrosis, late-onset diabetes mellitus, and numerous neurodegenerative diseases like Alzheimer's and Parkinson's. Nanoimaging technology has proved crucial in understanding protein-misfolding pathologies and in potential drug design aimed at the inhibition or reversal of protein aggregation. Using these technologies, researchers can monitor the aggregation process, visualize protein aggregates and analyze their properties. - Provides practical examples of nanoimaging research from leading molecular biology, cell biology, protein chemistry, biotechnology, genetics, and pharmaceutical labs - Includes over 200 color images to illustrate the power of various nanoimaging technologies - Focuses on nanoimaging techniques applied to protein misfolding and aggregation in molecular medicine
The second volume continues to fill the gap in protein review and protocol literature. It does this while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. The focus of Part B is the molecular basis of differential disorders.
This volume has a strong focus on homo-oligomerization, which is surprisingly common. However, protein function is so often linked to both homo- and hetero-oligomerization and many heterologous interactions likely evolved from homologous interaction, so this volume also covers many aspects of hetero-oligomerization.
