Protein Misfolding In Neurodegenerative Diseases

Research focused on protein folding, misfolding, and aggregation is leading to major advances across biochemistry and medicine. The elucidation of a folding code is proving to be of extreme importance in the postgenomic era, where a number of orphan genes have been identified for which no clear function has yet been established. This research is starting to shed light on the molecular and biochemical basis of a number of neurodegenerative diseases of dramatic impact. Protein Misfolding in Neurodegenerative Diseases: Mechanisms and Therapeutic Strategies addresses key issues concerning protein misfolding and aggregation in neurodegenerative diseases. Building on recent developments, including the recognition of protein misfolding as both a marker and a causal agent, the text presents the work of those who are actively pursuing more effective treatments, as well as preventative measures, and a possible cure. These include the use of molecular chaperones to control misfolding and novel pharmaceuticals, as well as the potential role of various inhibitors and NSAIDS. A Comprehensive Multifaceted Examination of the Complex Causal Agents Implicated in Protein Misfolding Divided into five sections, this groundbreaking text provides up-to-date accounts for Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis and Transmissible Spongiform Encephalitis. It also explores the highly likelihood that multiple factors, including oxidative stress, play a role in these complex diseases.

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Offering all the latest in the study of neurodegenerative diseases, this book reviews the molecular events initiated by unfolded or misfolded proteins leading to conformational human diseases, especially those found in Parkinson’s and Alzheimer’s diseases.

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

The health of the proteome depends upon protein quality control to regulate the proper synthesis, folding, translocation, and clearance of proteins. The cell is challenged constantly by environmental and physiological stress, aging, and the chronic expressions of disease associated misfolded proteins. Substantial evidence supports the hypothesis that the expression of damaged proteins initiates a cascade of molecular events that leads to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and other diseases of protein conformation.

The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms presents the pathology, genetics, biochemistry and cell biology of the major human neurodegenerative diseases, including Alzheimer’s, Parkinson’s, frontotemporal dementia, ALS, Huntington’s, and prion diseases. Edited and authored by internationally recognized leaders in the field, the book's chapters explore their pathogenic commonalities and differences, also including discussions of animal models and prospects for therapeutics. Diseases are presented first, with common mechanisms later. Individual chapters discuss each major neurodegenerative disease, integrating this information to offer multiple molecular and cellular mechanisms that diseases may have in common. This book provides readers with a timely update on this rapidly advancing area of investigation, presenting an invaluable resource for researchers in the field. Covers the spectrum of neurodegenerative diseases and their complex genetic, pathological, biochemical and cellular features Focuses on leading hypotheses regarding the biochemical and cellular dysfunctions that cause neurodegeneration Details features, advantages and limitations of animal models, as well as prospects for therapeutic development Authored by internationally recognized leaders in the field Includes illustrations that help clarify and consolidate complex concepts

This book discusses a broad range of basic and advanced topics in the field of protein structure, function, folding, flexibility, and dynamics. Starting with a basic introduction to protein purification, estimation, storage, and its effect on the protein structure, function, and dynamics, it also discusses various experimental and computational structure determination approaches; the importance of molecular interactions and water in protein stability, folding and dynamics; kinetic and thermodynamic parameters associated with protein-ligand binding; single molecule techniques and their applications in studying protein folding and aggregation; protein quality control; the role of amino acid sequence in protein aggregation; muscarinic acetylcholine receptors, antimuscarinic drugs, and their clinical significances. Further, the book explains the current understanding on the therapeutic importance of the enzyme dopamine beta hydroxylase; structural dynamics and motions in molecular motors; role of cathepsins in controlling degradation of extracellular matrix during disease states; and the important structure-function relationship of iron-binding proteins, ferritins. Overall, the book is an important guide and a comprehensive resource for understanding protein structure, function, dynamics, and interaction.

Human Caspases and Neuronal Apoptosis in Neurodegenerative Diseases elucidates elaborately the role of caspase enzymes implicated in the initiation of molecular events leading to neuronal apoptosis in the neurodegenerative disease. The book starts with introduction to neuropathology, neurogenetics, and epidemiology of neurodegenerative disease and illustrates the involvement of human caspases, neuronal apoptosis, apoptotic pathways, genetic polymorphisms, and several other factors and underlying mechanisms in the pathology of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. An important focus in all chapters is the intricate mechanisms and interplay that occur during or leading to neuron death in neurodegenerative diseases, along with disease pathobiology. Provides in-depth knowledge about neurotoxic potential of transition metals, impaired mitochondrial dynamics in the brain neurons, mutant proteins Aß peptide, tau protein, a-synuclein, huntingtin protein and formation of Lewy bodies, reactive oxygen and nitrogen species, ubiquitin proteasome dysregulation, and many others in neurodegenerative diseases Elucidates neurogenetics of gene APP, gene PSEN1, gene APOE, gene LRRK2, gene DJ1, and others in the pathology of neurodegenerative diseases Explains caspases-mediated neuronal apoptosis in pathogenesis of Alzheimer’s disease covering amyloidogenesis, caspase-activated DNase, rho-associated coiled coil–containing protein kinase 1, mammalian sterile 20-like kinase 1, role of synaptic loss, microglial TREM2 receptor, microglial LRP1 receptor, microglial advanced glycation end-product receptor, astrocytic glial a 7 subtypes of nAChR, NLRP3 inflammasome, P2X purinoreceptors, miRNAs, and many other factors Demonstrates the role of caspases and apoptosis in Parkinson’s disease covering truncation of a-synuclein, neuroinflammation, parkin protein, activation of microglial cells, extrinsic and intrinsic pathways of apoptosis, ?tau314, and several other factors Explains etiopathogenesis of Huntington’s disease through covering clinically important topics as role of exon 1 HTT protein, ubiquitous nature of huntingtin, length of expanded polyglutamine tract, classically and alternately activated microglia, nuclear factor kappa B, kynurenine signaling pathway, tumor suppressor protein, PGC-1a gene, advanced glycation end-products, autophagy, and many other significant topics