Protein Misfolding Diseases

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Author :
Publisher : John Wiley & Sons
ISBN 13 : 1118031814
Total Pages : 1311 pages
Book Rating : 4.1/5 (18 download)

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Book Synopsis Protein Misfolding Diseases by : Marina Ramirez-Alvarado

Download or read book Protein Misfolding Diseases written by Marina Ramirez-Alvarado and published by John Wiley & Sons. This book was released on 2010-12-01 with total page 1311 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Protein Misfolding in Neurodegenerative Diseases

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Author :
Publisher : CRC Press
ISBN 13 : 9781420007145
Total Pages : 592 pages
Book Rating : 4.0/5 (71 download)

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Book Synopsis Protein Misfolding in Neurodegenerative Diseases by : Robert D. E. Sewell

Download or read book Protein Misfolding in Neurodegenerative Diseases written by Robert D. E. Sewell and published by CRC Press. This book was released on 2007-12-03 with total page 592 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Protein Misfolding and Disease

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Author :
Publisher : Springer Science & Business Media
ISBN 13 : 1592593941
Total Pages : 317 pages
Book Rating : 4.5/5 (925 download)

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Book Synopsis Protein Misfolding and Disease by : Peter Bross

Download or read book Protein Misfolding and Disease written by Peter Bross and published by Springer Science & Business Media. This book was released on 2008-02-02 with total page 317 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases

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Author :
Publisher : Frontiers Media SA
ISBN 13 : 2889635074
Total Pages : 158 pages
Book Rating : 4.8/5 (896 download)

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Book Synopsis Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases by : Diana Fernandes Lázaro

Download or read book Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases written by Diana Fernandes Lázaro and published by Frontiers Media SA. This book was released on 2020-02-20 with total page 158 pages. Available in PDF, EPUB and Kindle. Book excerpt: This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.

Tau oligomers

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Publisher : Frontiers E-books
ISBN 13 : 288919261X
Total Pages : 114 pages
Book Rating : 4.8/5 (891 download)

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Book Synopsis Tau oligomers by : Jesus Avila

Download or read book Tau oligomers written by Jesus Avila and published by Frontiers E-books. This book was released on 2014-08-18 with total page 114 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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”.

Protein Folding, Misfolding, and Disease

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Author :
Publisher : Humana Press
ISBN 13 : 9781493956890
Total Pages : 249 pages
Book Rating : 4.9/5 (568 download)

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Book Synopsis Protein Folding, Misfolding, and Disease by : Andrew F. Hill

Download or read book Protein Folding, Misfolding, and Disease written by Andrew F. Hill and published by Humana Press. This book was released on 2016-08-23 with total page 249 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein misfolding is a key feature of many disorders in humans, given that over twenty proteins are known to misfold and cause disease. In Protein Folding, Misfolding, and Disease: Methods and Protocols, experts in the field present a collection of current methods for studying the analysis of protein folding and misfolding, featuring strategies for expressing and refolding recombinant proteins which can then be utilized in subsequent experiments. This detailed volume also covers methods for analyzing the formation of amyloid, protocols for determining the size and structure of native and misfolded proteins, as well as specific examples of where misfolded proteins can be examined using state-of –the-art technologies. Written in the highly successful Methods in Molecular BiologyTM series format, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and key tips on troubleshooting and avoiding known pitfalls. Up to date and authoritative, Protein Folding, Misfolding, and Disease: Methods and Protocols offers researchers the tools necessary to move ahead in this vital field.

Protein Folding and Metal Ions

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Author :
Publisher : CRC Press
ISBN 13 : 1439809658
Total Pages : 308 pages
Book Rating : 4.4/5 (398 download)

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Book Synopsis Protein Folding and Metal Ions by : Cláudio M. Gomes

Download or read book Protein Folding and Metal Ions written by Cláudio M. Gomes and published by CRC Press. This book was released on 2016-04-19 with total page 308 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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 and Metal Ions: Mechanisms, Biology and Disease presents the contributions of a cadre of international experts who offer a comprehensive exploration of this timely subject at the forefront of current research. Divided into four sections, this volume: Provides case study examples of protein folding and stability studies in particular systems or proteins that comprise different metal ions of co-factors Reviews the proteins that shuttle metal ions in the cell to a particular target metalloprotein Illustrates how metal binding can be connected to pathological protein conformations in unrelated diseases, from cancer to protein deposition disorders such as Parkinson’s disease Addresses protein redesign of metal-containing proteins by computational methods, folding simulation studies, and work on model peptides — dissecting the relative energetic contribution of metals sites to protein folding and stability Together, the 13 chapters in this text cogently describe the state of the science today, illuminate current challenges, propose future possibilities, and encourage further study in this area that offers much promise especially with regard to novel approaches to the treatment of some of the most challenging and tragic diseases.

Bio-nanoimaging

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Publisher : Academic Press
ISBN 13 : 0123978211
Total Pages : 552 pages
Book Rating : 4.1/5 (239 download)

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Book Synopsis Bio-nanoimaging by : Vladimir Uversky

Download or read book Bio-nanoimaging written by Vladimir Uversky and published by Academic Press. This book was released on 2013-11-05 with total page 552 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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

Frontiers in Protein Structure, Function, and Dynamics

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Author :
Publisher : Springer Nature
ISBN 13 : 9811555303
Total Pages : 458 pages
Book Rating : 4.8/5 (115 download)

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Book Synopsis Frontiers in Protein Structure, Function, and Dynamics by : Dev Bukhsh Singh

Download or read book Frontiers in Protein Structure, Function, and Dynamics written by Dev Bukhsh Singh and published by Springer Nature. This book was released on 2020-07-02 with total page 458 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Molecular Chaperones in Health and Disease

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Publisher : Springer Science & Business Media
ISBN 13 : 9783540258759
Total Pages : 464 pages
Book Rating : 4.2/5 (587 download)

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Book Synopsis Molecular Chaperones in Health and Disease by : Matthias Gaestel

Download or read book Molecular Chaperones in Health and Disease written by Matthias Gaestel and published by Springer Science & Business Media. This book was released on 2005-09-27 with total page 464 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Oxidative Stress and Redox Signalling in Parkinson’s Disease

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Author :
Publisher : Royal Society of Chemistry
ISBN 13 : 1782621881
Total Pages : 537 pages
Book Rating : 4.7/5 (826 download)

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Book Synopsis Oxidative Stress and Redox Signalling in Parkinson’s Disease by : Rodrigo Franco

Download or read book Oxidative Stress and Redox Signalling in Parkinson’s Disease written by Rodrigo Franco and published by Royal Society of Chemistry. This book was released on 2017-07-25 with total page 537 pages. Available in PDF, EPUB and Kindle. Book excerpt: Parkinson's Disease is the second most common neurodegenerative disorder affecting millions of people worldwide. In order to find neuroprotective strategies, a clear understanding of the mechanisms involved in the dopaminergic death of cells that progresses the disease is needed. Oxidative stress can be defined as an imbalance between the production of reactive species and the ability to detoxify them and their intermediates or by-products. Oxidative damage to lipids, proteins, and DNA has been detected in autopsies from individuals with Parkinson’s Disease and so links can be made between oxidative stress and Parkinson’s Disease pathogenesis. This book provides a thorough review of the mechanisms by which oxidative stress and redox signalling mediate Parkinson’s Disease. Opening chapters bring readers up to speed on basic knowledge regarding oxidative stress and redox signalling, Parkinson’s Disease, and neurodegeneration before the latest advances in this field are explored in detail. Topics covered in the following chapters include the role of mitochondria, dopamine metabolism, metal homeostasis, inflammation, DNA-damage and thiol-signalling. The role of genetics and gene-environment interactions are also explored before final chapters discuss the identification of potential biomarkers for diagnosis and disease progression and the future of redox/antioxidant based therapeutics. Written by recognized experts in the field, this book will be a valuable source of information for postgraduate students and academics, clinicians, toxicologists and risk assessment groups. Importantly, it presents the current research that might later lead to redox or antioxidant – based therapeutics for Parkinson’s disease.

Protein Misfolding Disorders

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Publisher : Bentham Science Publishers
ISBN 13 : 1608050130
Total Pages : 156 pages
Book Rating : 4.6/5 (8 download)

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Book Synopsis Protein Misfolding Disorders by : Claudio Hetz

Download or read book Protein Misfolding Disorders written by Claudio Hetz and published by Bentham Science Publishers. This book was released on 2009 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Prion-related disorders (PrD) and Huntington’s disease (HD) share a common neuropathology, primarily featuring the presence of abnormal protein inclusions containing specific misfolded proteins. These groups of diseases are now classified as Protein Misfolding Disorders. This book gives a comprehensive overview of the possible mechanisms involved in Protein Misfolding Disorders and possible therapeutic strategies to treat these diseases. The Ebook provides the most recent evidence addressing the role of cellular stress responses to neurological diseases, along with therapeutic strategies to alleviate ER stress in a disease context. -- Publisher.

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging

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Publisher : Academic Press
ISBN 13 : 0128094273
Total Pages : 430 pages
Book Rating : 4.1/5 (28 download)

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Book Synopsis Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging by : M. A. Hayat

Download or read book Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging written by M. A. Hayat and published by Academic Press. This book was released on 2016-12-28 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt: Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging is an eleven volume series that discusses in detail all aspects of autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. This series discusses the characterization of autophagosome-enriched vaccines and its efficacy in cancer immunotherapy. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward-thinking, these books offer a valuable guide to cellular processes while also inciting researchers to explore their potentially important connections. Presents the most advanced information regarding the role of the autophagic system in life and death Examines whether autophagy acts fundamentally as a cell survivor or cell death pathway or both Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation Features recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities, including atherosclerosis and CNS tumors, and their development and treatment Includes chapters authored by leaders in the field around the globe—the broadest, most expert coverage available

Protein Misfolding, Aggregation and Conformational Diseases

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Author :
Publisher : Springer Science & Business Media
ISBN 13 : 0387365346
Total Pages : 538 pages
Book Rating : 4.3/5 (873 download)

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Book Synopsis Protein Misfolding, Aggregation and Conformational Diseases by : Vladimir N. Uversky

Download or read book Protein Misfolding, Aggregation and Conformational Diseases written by Vladimir N. Uversky and published by Springer Science & Business Media. This book was released on 2007-05-26 with total page 538 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Protein Misfolding, Aggregation and Conformational Diseases

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Author :
Publisher : Springer Science & Business Media
ISBN 13 : 0387259198
Total Pages : 419 pages
Book Rating : 4.3/5 (872 download)

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Book Synopsis Protein Misfolding, Aggregation and Conformational Diseases by : Vladimir N. Uversky

Download or read book Protein Misfolding, Aggregation and Conformational Diseases written by Vladimir N. Uversky and published by Springer Science & Business Media. This book was released on 2007-11-24 with total page 419 pages. Available in PDF, EPUB and Kindle. Book excerpt: Research indicates that most neurodegenerative diseases, systemic amyloidoses and many others, arise from the misfolding and aggregation of an underlying protein. This is the first book to discuss significant achievements in protein structure-function relationships in biochemistry, molecular biology and molecular medicine. The authors summarize recent progress in the understanding of the relationships between protein misfolding, aggregation and development of protein deposition disorders.

Neurodegeneration

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Author :
Publisher : National Academies Press
ISBN 13 : 9780309285674
Total Pages : 0 pages
Book Rating : 4.2/5 (856 download)

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Book Synopsis Neurodegeneration by : Forum on Neuroscience and Nervous System Disorders

Download or read book Neurodegeneration written by Forum on Neuroscience and Nervous System Disorders and published by National Academies Press. This book was released on 2013-12-26 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Neurodegeneration: Exploring Commonalities Across Diseases is the summary of a workshop hosted by the Institute of Medicine\'s (IOM\'s) Forum on Neuroscience and Nervous System Disorders in Spring 2012 to explore commonalities across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Participants from academia; pharmaceutical and biotechnology industries; government agencies such as the National Institutes of Health and the U.S. Department of Veterans Affairs (VA); patient advocacy groups; and private foundations presented and identified potential opportunities for collaboration across the respective research and development communities. This report identifies and discusses commonalities related to genetic and cellular mechanisms, identifies areas of fundamental science needed to facilitate therapeutics development, and explores areas of potential collaboration among the respective research communities. Neurodegenerative diseases, such as Alzheimer\'s disease, Parkinson\'s disease, ALS, and FTD, are becoming increasingly prevalent in the United States due to an aging population. Implications are grave for quality of life and health care costs. Research on neurodegenerative diseases has expanded greatly over the past four decades. Nevertheless, fundamental questions remain about the biology of these diseases, and further insights into the mechanisms of these diseases would help to inform the development of effective means to prevent and to efficiently treat them. Recent findings have revealed certain commonalities in genetic and cellular mechanisms across neurodegenerative diseases. These findings suggest that it might be valuable - at least in some cases - to change the traditional way of studying these diseases by no longer seeing each as an independent entity, but rather as clinical variants of common cellular and molecular biological defects. This approach could help enhance basic scientific understanding of neurodegenerative disease, and could help with the development of biomarkers and new therapeutics.

Protein folding and misfolding: neurodegenerative diseases

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Author :
Publisher : Springer Science & Business Media
ISBN 13 : 1402094345
Total Pages : 284 pages
Book Rating : 4.4/5 (2 download)

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Book Synopsis Protein folding and misfolding: neurodegenerative diseases by : Judit Ovádi

Download or read book Protein folding and misfolding: neurodegenerative diseases written by Judit Ovádi and published by Springer Science & Business Media. This book was released on 2008-12-21 with total page 284 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.