Amyloid And Lysozyme Proteotoxicity In Drosophila
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Author | : Liza Bergkvist |
Publisher | : Linköping University Electronic Press |
Total Pages | : 91 |
Release | : 2017-05-16 |
Genre | : |
ISBN | : 9176855066 |
In the work presented this thesis, two different conditions that are classified as protein misfolding diseases: Alzheimer's disease and lysozyme amyloidosis and proteins that could have a beneficial effect in these diseases, have been studied using Drosophila melanogaster, commonly known as the fruit fly. The fruit fly has been used for over 100 years to study and better understand fundamental biological processes. Although the fruit fly, unlike humans, is an invertebrate, many of its central biological mechanisms are very similar to ours. The first transgenic flies were designed in the early 1980s, and since then, the fruit fly has been one of the most widely used model organisms in studies on the effects of over-expressed human proteins in a biological system; one can regard the fly as a living, biological test tube. For most proteins, it is necessary that they fold into a three-dimensional structure to function properly. But sometimes the folding goes wrong; this may be due to mutations that make the protein unstable and subject to misfolding. A misfolded protein molecule can then aggregate with other misfolded proteins. In Alzheimer's disease, which is the most common form of dementia, protein aggregates are present in the brains of patients. These aggregates are composed of the amyloid-? (A?) peptide, a small peptide of around 42 amino acids which is cleaved from the larger, membrane-bound, protein A?PP by two different enzymes, BACE1 and ?-secretase. In the first part of this thesis, two different fly models for Alzheimer’s disease were used: the A? fly model, which directly expresses the A? peptide, and the A?PP-BACE1 fly model, in which all the components necessary to produce the A? peptide in the fly are expressed in the fly central nervous system (CNS). The two different fly models were compared and the results show that a significantly smaller amount of the A? peptide is needed to achieve the same, or an even greater, toxic effect in the A?PP-BACE1 model compared to the A? model. In the second part of the thesis, these two fly models for Alzheimer’s disease were again used, but now to investigate whether lysozyme, a protein involved in our innate immune system, can counteract the toxic effect of A? generated in the fly models. And indeed, lysozyme is able to save the flies from A?-induced toxicity. A? and lysozyme were found to interact with each other in vivo. The second misfolding disease studied in this thesis is lysozyme amyloidosis. It is a rare, dominantly inherited amyloid disease in which mutant variants of lysozyme give rise to aggregates, weighing up to several kilograms, that accumulate around the kidneys and liver, eventually leading to organ failure. In the third part of this thesis, a fly model for lysozyme amyloidosis was used to study the effect of co-expressing the serum amyloid P component (SAP), a protein that is part of all protein aggregates found within this disease class. SAP is able to rescue the toxicity induced by expressing the mutant variant of lysozyme, F57I, in the fly's CNS. To further investigate how SAP was able to do this, double-expressing lysozyme flies, which exhibit stronger disease phenotypes than those of the single-expressing lysozyme flies previously studied, were used in the fourth part of this thesis. SAP was observed to reduce F57I toxicity and promote F57I to form aggregates with more distinct amyloid characteristics. In conclusion, the work included in this thesis demonstrates that: i) A? generated from A?PP processing in the fly CNS results in higher proteotoxicity compared with direct expression of A? from the transgene, ii) lysozyme can prevent A? proteotoxicity in Drosophila and could thus be a potential therapeutic molecule to treat Alzheimer’s disease and iii) in a Drosophila model of lysozyme amyloidosis, SAP can prevent toxicity from the disease-associated lysozyme variant F57I and promote formation of aggregated lysozyme morphotypes with amyloid properties; this is important to take into account when a reduced level of SAP is considered as a treatment strategy for lysozyme amyloidosis.
Author | : Marina Ramirez-Alvarado |
Publisher | : John Wiley & Sons |
Total Pages | : 1311 |
Release | : 2010-12-01 |
Genre | : Science |
ISBN | : 1118031814 |
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.
Author | : |
Publisher | : Elsevier |
Total Pages | : 520 |
Release | : 2018-06-07 |
Genre | : Medical |
ISBN | : 0444639535 |
Human Prion Diseases, Volume 153 is designed to update the reader on the latest advances and clinical aspects of prion diseases. The book is organized into five sections, including the pathophysiology of prions and a description of animal and human diseases. This is followed by detailed reports on recent advances in diagnosis strategies for the development of novel anti-prion molecules and possible designs of clinical trials in such a rare disease. An introductory chapter gives an extensive historical background of prion research, with a final chapter highlighting recent progress, and more importantly, unsolved problems. - Offers an authoritative overview of prion diseases in humans, detailing the pathogenesis of the disease, clinical investigations, and the diagnosis of both the genetic and acquired forms - Provides clarity and context by presenting prion diseases in relation to other neurodegenerative diseases in humans - Emphasizes the unique properties of prion diseases and consequent problems they can cause, both clinically and in public health terms
Author | : Gaspar Banfalvi |
Publisher | : Springer Science & Business Media |
Total Pages | : 348 |
Release | : 2011-03-02 |
Genre | : Medical |
ISBN | : 9400704283 |
The term “heavy metals” is used as a group name of toxic metals and metalloids (semimetals) causing contaminations and ecotoxicity. In strict chemical sense the density of heavy metals is higher than 5 g/cm3. From biological point of view as microelements they can be divided into two major groups. a. For their physiological function organisms and cells require essential microelements such as iron, chromium (III), cobalt, copper, manganese, molidenium, zinc. b. The other group of heavy metals is toxic to the health or environment. Of highest concern are the emissions of As, Cd, Co, Cu, Hg, Mn, Ni, Pb, Sn, Tl. The toxicity of heavy metals is well known at organizational level, while less attention has been paid to their cellular effects. This book describes the toxicity of heavy metals on microorganisms, yeast, plant and animal cells. Other chapters of the book deal with their genotoxic, mutagenic and carcinogenic effects. The toxicity of several metals touch upon the aspects of environmental hazard, ecosystems and human health. Among the cellular responses of heavy metals irregularities in cellular mechanisms such as gene expression, protein folding, stress signaling pathways are among the most important ones. The final chapters deal with biosensors and removal of heavy metals. As everybody is eating, drinking and exposed to heavy metals on a daily basis, the spirit of the book will attract a wide audience.
Author | : Jesus Avila |
Publisher | : Frontiers E-books |
Total Pages | : 114 |
Release | : 2014-08-18 |
Genre | : Medicine (General) |
ISBN | : 288919261X |
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”.
Author | : Frederick R. Maxfield |
Publisher | : John Wiley & Sons |
Total Pages | : 586 |
Release | : 2016-06-22 |
Genre | : Medical |
ISBN | : 1118978315 |
Discussing recent findings, up-to-date research, and novel strategies, the book integrates perspectives from pharmacology, toxicology, and biochemistry to illustrate the potential of lysosomes in drug discovery and development. • Explores basic principles and properties of lysosomes that allow them to act as regulators of cell metabolism, therapeutic targets, and sites for activation of drug conjugates • Discusses the role of lysosomes in metabolism, drug targeting, apoptosis, cancer, aging, inflammation, autophagy, metabolism, toxicity, and membrane repair • Introduces new pathways in therapeutic development and new mechanisms in drug development
Author | : Robert M. Tanguay |
Publisher | : Springer |
Total Pages | : 603 |
Release | : 2015-06-15 |
Genre | : Medical |
ISBN | : 331916077X |
Based upon a workshop entitled “The Small HSP World” held in Québec 2-5 October 2014. Twenty-five scientists provided chapters for the book. The chapters are from the best scientists currently working in this field. These colleagues include Arrigo, Benesch, Benjamin, Buchner-Haslbeck-Weinkauf, Benndorf, Boelens, Carra, Chang, Currie, Ecroyd, Emanuelsson, Fu, Garrido, Golenhofen, Gusev, Hightower, Kampinga, Lavoie, MacRae, Quinlan, Tanguay, Vierling, Vigh, Weeks and Wu. Briefly, the book starts with the structure of small heat shock proteins, moving to their functions and finishing with their involvement in diseases. Although this is quite broad, the structural aspect will be the unifying theme of the book.
Author | : Michael S. Wolfe |
Publisher | : Academic Press |
Total Pages | : 561 |
Release | : 2018-03-29 |
Genre | : Medical |
ISBN | : 0128113057 |
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
Author | : Laishram Rajendrakumar Singh |
Publisher | : Springer |
Total Pages | : 0 |
Release | : 2024-10-12 |
Genre | : Science |
ISBN | : 9789819760008 |
The second edition of this book presents the role of osmolytes in human health and diseases. Some of the chapters deal about the possibility of the use of osmolytes as diagnostic biomarkers and potential drug design for neurodegenerative and other human diseases. Other chapters also include reviews on the role of osmolytes in cancer, metastasis, infectious diseases, metabolic disorders, immunological disorders, and tissue regeneration. Importantly, the book also contain recent updates on the role of naturally occurring osmolytes in protein folding pathway, protein stability, and their underlying mechanisms. The book also covers the aspects that osmolytes could promote conformational alterations of transcription factors that favor metastatic behavior. Potential of the osmolytes in the various process of vaccine development, including enhancing the efficacy, production, and purification steps are also succintly described. Towards the end, the book also elucidates the use of specific molecules for the prevention of toxic gain of functions and restoration of function to disease-causing mutant protein. This book is an invaluable asset for the researchers especially working in osmolyte biology and scientists involved in basic and clinical research particularly neurodegeneration, diabetes, cancer, and metabolic disorders.
Author | : Ved Srivastava |
Publisher | : Royal Society of Chemistry |
Total Pages | : 589 |
Release | : 2017-06-26 |
Genre | : Medical |
ISBN | : 1782627324 |
With potentially high specificity and low toxicity, biologicals offer promising alternatives to small-molecule drugs. Peptide therapeutics have again become the focus of innovative drug development efforts backed up by a resurgence of venture funds and small biotechnology companies. What does it take to develop a peptide-based medicine? What are the key challenges and how are they overcome? What are emerging therapeutics for peptide modalities? This book answers these questions with a holistic story from molecules to medicine, combining the themes of design, synthesis and clinical applications of peptide-based therapeutics and biomarkers. Chapters are written and edited by leaders in the field from industry and academia and they cover the pharmacokinetics of peptide therapeutics, attributes necessary for commercially successful metabolic peptides, medicinal chemistry strategies for the design of peptidase-resistant peptide analogues, disease classes for which peptide therapeutic are most relevant, and regulatory issues and guidelines. The critical themes covered provide essential background information on what it takes to develop peptide-based medicine from a chemistry perspective and views on the future of peptide drugs. This book will be a valuable resource not only as a reference book for the researcher engaged in academic and pharmaceutical setting, from basic research to manufacturing and from organic chemistry to biotechnology, but also a valuable resource to graduate students to understand discovery and development process for peptide-based medicine.