Proteostasis And Disease

This book, written by members of the European network PROTEOSTASIS, provides an up-to-date review of the research regarding protein homeostasis in health and disease. With new discoveries contributing to the increasing complexity of this topic, the book offers a detailed overview of the pathways regulating protein homeostasis, including autophagy and the ubiquitin protein family. Following a basic introduction, it explains how defects in protein homeostasis contribute to numerous pathologies, including cancer, neurodegeneration, inflammation and a number of rare diseases. In addition, it discusses, the role of protein homeostasis in cellular development and physiology. Highlighting the latest research in the field of protein homeostasis and its implications for various clinically relevant diseases, the book appeals to researchers and clinicians, while also offering a reference guide for scholars who are new to the field.

Proper folding of proteins is crucial for cell function. Chaperones and enzymes that post-translationally modify newly synthesized proteins help ensure that proteins fold correctly, and the unfolded protein response functions as a homeostatic mechanism that removes misfolded proteins when cells are stressed. This book covers the entire spectrum of proteostasis in healthy cells and the diseases that result when control of protein production, protein folding, and protein degradation goes awry.

The entire life cycle of a protein-from synthesis and folding to transport and degradation-is carefully controlled by the proteostasis network. This network, consisting of many interconnected pathways and processes, manages protein homeostasis by dynamically responding to the needs of the cell. Stress and aging can challenge the proteostasis network, resulting in the aggregation of misfolded proteins-a feature of numerous neurodegenerative conditions. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Biology provides a comprehensive update on how the proteostasis network functions in healthy cells and the diseases that result when protein quality control goes awry. The contributors examine the relevant biochemical attributes of proteins (e.g., solubility), the functions of normal protein aggregates (e.g., biofilm formation in bacteria), and the various heat shock proteins, chaperones, translocation machineries, proteasomes, signaling factors, and transcriptional programs involved in proteostasis. The roles of specific subcellular structures-the endoplasmic reticulum, mitochondria, ribosomes, lysosomes, and cytoplasm-in protein quality control are covered, as is the regulation of proteostasis at the organismal level (e.g., via neuronal activity). Discussions of the responses by cells when errors in protein quality control occur, the medical disorders that can result (e.g., Alzheimer disease), and pharmacologic approaches to ameliorate protein conformational disorders are also included. This book is therefore an essential reference for biochemists, cell biologists, and all biomedical scientists wishing to understand the pathological consequences of and potential therapies for proteostasis deficiencies in common human diseases.

Proteostasis is central to the development of various human diseases caused due to excessive protein misfolding and the disregulation of the protein quality control system. In this book, respected researchers from many leading institutions contribute their insights on proteostasis maintenance. The coverage mainly focuses on the basics of maintaining proteostasis, the consequences of proteostatic system failure, and how chaperone systems constantly maintain proteostasis. In addition, the book presents in detail different treatment strategies for diseases caused by proteostatic system failure, as well as the inhibition of proteostatic failure using small molecule compounds. It examines advances in the modulation of proteopathies, providing a comprehensive source of key mechanistic insights on these diseases. As such, the book offers a valuable resource for beginners and more experienced investigators alike who are looking for detailed and reliable information on protein homeostasis, the diseases that can develop due to related imbalances and the essential role of molecular and chemical chaperones.

"Proteins are the key decision-making workforce for practically all cellular signals. The precise equilibrium between protein translation, folding, function and timely degradation, also known as "proteostasis", determine cellular health as well as organismal maintenance and survival. Loss of cellular proteostasis is linked with physiological processes of deterioration such as aging, with conditions characterized by supraphysiological oxidative stress as well as with illness, including age-related diseases, neurodegeneration, inflammation, dystrophies and cancer. This book includes 18 chapters logically organized to allow comprehensive understanding of how maintenance of proteostasis protects cellular and organismal health, and how environmental and metabolic pressure can impair proteostasis and lead to disequilibrium and disease. Each chapter contains up-to-date information on its respective topic while some of them review the interplay of certain proteostatic mechanisms, a newly arising topic. Importantly, most chapters include tangible examples of how failure of proteostasis can underlie aging and disease. We hope that the compilation of the above topics will assist both novice and experienced researchers and students to become more familiar with the subject of proteostasis. In the long run, we hope that this book will inspire its readers and eventually promote new ideas and new research studies"--

Protein homeostasis, or “Proteostasis”, lies at the heart of human health and disease. From the folding of single polypeptide chains into functional proteins, to the regulation of intracellular signaling pathways, to the secreted signals that coordinate cells in tissues and throughout the body, the proteostasis network operates to support cell health and physiological fitness. However, cancer cells also hijack the proteostasis network and many of these same processes to sustain the growth and spread of tumors. The chapters in this book are written by world experts in the many facets of the proteostasis network. They describe cutting-edge insights into the structure and function of the major chaperone and degradation systems in healthy cells and how these systems are co-opted in cancer cells and the cells of the tumor microenvironment. The chapters also cover therapeutic interventions such as the FDA-approved proteasome inhibitors Velcade and Krypolis as well as other therapies currently under clinical investigation to disarm the ability of the proteostasis network to support malignancy. This compendium is the first of its kind and aims to serve as a reference manual for active investigators and a primer for newcomers to the field. This book is dedicated to the memory of Susan Lindquist, a pioneer of the proteostasis field and a champion of the power of basic scientific inquiry to unlock the mechanisms of human disease. The chapter “Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective” is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

Since Alois Alzheimer described the results of his postmortem studies in 1906, significant strides have been made in understanding the pathogenesis of neurodegenerative diseases. Substantial evidence has accumulated indicating that diverse neurodegenerative disorders might share a common pathological mechanism: the misfolding, aggregation and accumulation of proteins (termed "amyloid") in the brain. Metal ions have long been thought to catalyze protein misfolding initiating a cascade of events resulting in oxidative damage and neurodegeneration. They have, consequently, been seen as a suitable pharmacological target. However, drugs aimed at simply removing excess metals or interfering in amyloid deposition were unsuccessful and scientists have been forced to review the classical hypothesis. The latest advances suggest that deficiencies in protein homeostasis may lead to cell dysfunction and disease. Furthermore, small molecules with the potential to control metal homeostasis, or metallostasis, are expected to provide the framework for the design of novel proteostasis regulators. This book provides an up-date on the latest developments in this fast moving field. Traditional views concerning the relationship between the physio-pathological cycles of copper, zinc, iron, aluminium and the evolution of life, are compared with emerging ideas in the neuroscience of metal ions. Topics covered emphasize the importance of metals and oxidation chemistry to neuroscientists as well as providing a wider, multidisciplinary background to chemists who are attracted by these fascinating subjects. The text starts with a chapter on chemical evolution, the brain and metallomics which describes the brain's natural defences to adverse conditions. It then goes on to cover the chemistry and biology of proteostasis, environmental factors, and the role played by membranes in protein misfolding. The remaining chapters cover the role of metals and oxidative stress in Alzheimer's Disease, Parkinsonism, ALS and other neurodegenerative diseases. The book is suitable for academics, those working in industry, and postgraduate students.

Protein Homeostasis Diseases: Mechanisms and Novel Therapies offers an interdisciplinary examination of the fundamental aspects, biochemistry and molecular biology of protein homeostasis disease, including the use of natural and pharmacological small molecules to treat common and rare protein homeostasis disorders. Contributions from international experts discuss the biochemical and genetic components of protein homeostasis disorders, the mechanisms by which genetic variants may cause loss-of-function and gain-of-toxic-function, and how natural ligands can restore protein function and homeostasis in genetic diseases. Applied chapters provide guidance on employing high throughput sequencing and screening methodologies to develop pharmacological chaperones and repurpose approved drugs to treat protein homeostasis disorders. Provides an interdisciplinary examination of protein homeostasis disorders, with an emphasis on treatment strategies employing small natural and pharmacological ligands Offers applied approaches in employing high throughput sequencing and screening to develop pharmacological chaperones to treat protein homeostasis disease Gathers expertise from a range of international chapter authors who work across various biological methods and disease specific disciplines of relevance