Protein Homeostasis Diseases: Mechanisms and Novel Therapies

Description

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. Chapter 1 - Protein folding: how, why, and beyond Outline Introduction Protein conformational landscapes Mutational perturbations to probe folding mechanisms and function Disordered proteins-regions and unfolded states Folding, stability, and binding in vivo “Real proteins” and beyond Acknowledgments References Chapter 2 - Protein homeostasis and disease Outline Abbreviations Protein folding in vitro and in vivo Effects of intracellular milieu composition on protein folding, misfolding, and stability in vivo The first steps of in vivo folding and misfolding in the ribosomes: cotranslational versus posttranslational processes Protein homeostasis networks Molecular chaperones Protein degradation: proteasome versus autophagy Human misfolding diseases Loss-of-function diseases Gain-of-toxic function diseases Acknowledgments Conflict of interest Funding References Chapter 3 - Caenorhabditis elegans as a model organism for protein homeostasis diseases Outline Abbreviations Caenorhabditis elegans as a model organism The proteostasis network is conserved in Caenorhabditis elegans The heat shock response The unfolded protein response of the endoplasmic reticulum and the mitochondria The insulin-like signaling pathway Caenorhabditis elegans as a model for protein misfolding diseases Alzheimer’s disease Disease mechanism Caenorhabditis elegans Amyloid-β models Utility of Caenorhabditis elegans Alzheimer’s disease models for drug discovery and identification of genetic modifiers Tauopathies Disease mechanism Caenorhabditis elegans models of tauopathy Utility of Caenorhabditis elegans tauopathy models for drug discovery and identification of genetic modifiers Parkinson’s disease Disease mechanism Caenorhabditis elegans Parkinson’s disease models Utility of Caenorhabditis elegans Parkinson’s disease models for drug discovery and identification of genetic modifiers Polyglutamine diseases Disease mechanism Caenorhabditis elegans models of Huntington’s disease Utility of Caenorhabditis elegans HD models for drug discovery and identification of genetic modifiers Caenorhabditis elegans models of spinocerebellar ataxia Utility of Caenorhabditis elegans spinocerebellar ataxia models for drug discovery and identification of genetic modifiers Amyotrophic lateral sclerosis Disease mechanism Caenorhabditis elegans models of amyotrophic lateral sclerosis Transthyretin amyloidosis Disease mechanism Caenorhabditis elegans disease models of transthyretin amyloidosis Type II diabetes mellitus Disease mechanism Caenorhabditis elegans model of diabetes mellitus Dialysis-related amyloidosis Disease mechanism Immunoglobulin light chain amyloidosis Disease mechanism Caenorhabditis elegans models of immunoglobulin light chain amyloidosis Prion diseases Conclusion References Chapter 4 - Proteome-scale studies of protein stability Outline Abbreviations Introduction Protein stability and unfolding Biophysical methods to measure protein stability in vitro Protein stability in vivo Biological readouts to measure protein stability Proteome-scale analysis based on aggregation in vivo Proteome-scale analysis based on degradation in vivo Structural analyses of proteins and proteomes Cross-linking-based mass spectrometry Hydroxyl radical footprinting (HRF) Limited proteolysis-based mass spectrometry Proteome-scale methods involving experimental denaturation of proteins Denaturation probed by proteolysis sensitivity Thermal denaturation probed by aggregation Denaturation probed by methionine oxidation Contributions to basic and applied biomedical research Conclusions Acknowledgments References Chapter 5 - Classifying disease-associated variants using measures of protein activity and stability Outline Abbreviations Introduction Selection of PTEN variants Comparing multiplexed assays and computational predictions to assess variant effects Loss of stability is a major source for loss of PTEN function Conclusions Methods Rosetta ∆∆G calculations Evolutionary sequence energies (Ẽ) Phosphatase-MAVE and VAMP-seq data Determining thresholds from receiver operating characteristic curves Analysis scripts Acknowledgments References Chapter 6 - Protein destabilization and degradation as a mechanism for hereditary disease Outline Abbreviations Introduction to protein quality control Protein quality control in hereditary diseases Protein folding and refolding Protein quality control–mediated degradation via the ubiquitin-proteasome system Protein quality control degrons Local versus global unfolding Potential therapeutic approaches to protein quality control–linked hereditary diseases Acknowledgments Conflict of interest Funding References Chapter 7 - Detection of amyloid aggregation in living systems Outline Abbreviations Introduction Techniques for detection of amyloid aggregation in vivo Förster resonance energy transfer detection and fluorescence lifetime imaging Bioluminescence imaging Optical fiber bundles and fluorescence imaging Cranial window or thinned-skull imaging using multiphoton microscopy In vivo microdialysis Positron emission tomography imaging Animal models to test in vivo amyloid formation Caenorhabditis elegans Zebrafish Mouse models Note on using animal models for in vivo protein aggregation studies In vivo complexity and how do in vivo detection assays provide insight into peripheral aspects contributing to neurodegener... Replicating the multicellular complexity of the brain Interaction of the brain with the periphery system Future outlook Acknowledgments References Chapter 8 - Molecular mechanisms of amyloid aggregation in human proteinopathies Outline Introduction Protein aggregates: from dynamic oligomers to amyloid fibrils Amyloid fibrils Oligomers Protofibrils Mechanisms of amyloid aggregation Nucleation-Polymerization Nucleated conformational conversion More general mechanisms Application to different disease-related proteins Amyloid β peptides α-Synuclein hIAPP/amylin Concluding remarks Acknowledgments References Chapter 9 - Metals and amyloid gain-of-toxic mechanisms in neurodegenerative diseases Outline Abbreviations Metal ions and amyloid formation in neurodegeneration Protein misfolding and metal ions in neurodegeneration Trace metal import and homeostasis in the brain Zinc and toxic protein aggregates in Alzheimer’s disease Zinc dyshomeostasis in Alzheimer’s disease Zinc binding and aggregation of Aβ Zinc binding to Aβ Influence of zinc on Aβ aggregation Zinc binding and tau aggregation Zinc binding to tau Influence of zinc on tau aggregation Metal chelation therapies Acknowledgments References Chapter 10 - Vitamin B6-dependent enzymes and disease Abbreviations Clinical and genetic bases of misfolding diseases and natural ligand therapies Vitamin B6 enzymes and disease Primary hyperoxaluria type 1 due to deficiency of AGT Clinical and genetic features Molecular mechanisms leading to the AGT deficit in primary hyperoxaluria type 1 The role of natural and unnatural ligands as chaperones for AGT Steps forward to new therapeutic approaches for primary hyperoxaluria type 1 Conclusions Acknowledgments References Chapter 11 - Galactosemia: opportunities for novel therapies Outline Abbreviations Introduction: four types of galactosemia Causes of pathology and current treatment Potential novel therapies Pharmacological chaperones for GALT deficiency Pharmacological chaperones for other types of galactosemia Conclusions Acknowledgments References Chapter 12 - Protein homeostasis and regulation of intracellular trafficking of G protein-coupled receptors Outline Introduction Proteostasis and quality control systems Proteostasis Quality control systems Regulation of anterograde G protein-coupled receptor traffic from the endoplasmic reticulum to the cell surface plasma membrane Sequence motifs that promote/prevent upward trafficking of G protein-coupled receptors Posttranslational modifications in G protein-coupled receptors and intracellular trafficking Association of G protein-coupled receptors and intracellular trafficking Intracellular G protein-coupled receptor trafficking from the cell surface plasma membrane and beyond G protein-coupled receptor internalization via clathrin-coated pits and a central role of arrestins Divergent sorting of internalized G protein-coupled receptors and impact on receptor activity Sorting of G protein-coupled receptors to the regulated recycling pathway via multiple endosome types Sorting of G protein-coupled receptors to the lysosome Multilocation signaling of G protein-coupled receptors within the endocytic network Targeting misfolded G protein-coupled receptors with pharmacological chaperones Conclusions Acknowledgments References Chapter 13 - Structure-guided discovery of pharmacological chaperones targeting protein conformational and misfolding diseases Outline Abbreviations Introduction The premise and promise of pharmacological chaperone therapy Advances in protein structural biology Structure-guided understanding of disease-causing variants Variants leading to decreased flexibility Variants leading to increased flexibility Variants that alter cofactor or substrate binding Variants that alter binding interface Structural basis of pharmacological chaperoning Active-site inhibitory pharmacological chaperones for lysosomal storage disorders Starting points for allosteric pharmacological chaperones Pharmacological chaperones for defects in channels, transporters, and receptors Pharmacological chaperones for structural proteins Structural methods used in primary compound screening Fragment-based approach Crystallography-based screening Concluding remarks Statements Acknowledgments References Chapter 14 - Virtual screening in drug discovery: a precious tool for a still-demanding challenge Outline Abbreviations Introduction: the drug discovery process Accurate determination of binding affinity in a receptor–ligand complex Speeding up the search process through approximate scoring functions From binding properties to the identification of molecular descriptors Organizing distinct simulation techniques into a screening protocol References Chapter 15 - Differential scanning fluorimetry in the screening and validation of pharmacological chaperones for soluble and membrane pr... Outline Abbreviations Background Initial high-throughput screening by differential scanning fluorimetry Differential scanning fluorimetry–monitored screening for soluble proteins Experimental setup Data analysis Filtering of hits Validation of primary hits by concentration-dependent differential scanning fluorimetry Differential scanning fluorimetry–monitored screening for membrane proteins Experimental setup Conclusion Acknowledgments References Chapter 16 - Cellular high-throughput screening Outline Abbreviations: Introduction Cellular high-throughput screening Assay types Primary screen Negative screen Counter screen Positive control compound Pharmacoperone types Compound toxicity Genetic diseases potentially amenable to treatment with chemical or pharmacological chaperones: G protein-coupled receptors... G protein-coupled receptors Enzyme diseases Ion channel diseases Lysosomal storage disorders Challenges of high-throughput screening “hits” Conclusion Acknowledgments References Chapter 17 - High-throughput screening for intrinsically disordered proteins by using biophysical methods Outline Abbreviations Introduction Drug discovery and biophysics Biophysical techniques and high-throughput screening Intrinsically disordered proteins Fluorescence Introduction to fluorescence Fluorescence intensity Fluorescence polarization or anisotropy Fluorescence resonance energy transfer Fluorescence temperature-related intensity change Fluorescence-based high-throughput screening: thermal shift assay Nuclear magnetic resonance Introduction to nuclear magnetic resonance Ligand-based nuclear magnetic resonance screening methods Relaxation-based methods Nuclear Overhauser effect-based methods Saturation transfer difference (STD) between protein and ligand via nuclear Overhauser effects Transfer of 1H-polarization from water to the ligand Target-based nuclear magnetic resonance screening methods Surface plasmon resonance Applications of biophysical techniques to hit identification and validation for intrinsically disordered proteins Funding References Chapter 18 - Natural and pharmacological chaperones against accelerated protein degradation: uroporphyrinogen III synthase and congenita... Outline Abbreviations Introduction Heme group biosynthesis Uroporphyrinogen III synthase Congenital erythropoietic porphyria The UROIIIS “stability defect” analyzed in vitro UROIIIS is a kinetically stable protein Congenital erythropoietic porphyria–causing mutations accelerate protein degradation in vitro The irreversible unfolding of UROIIIS and the structure of the aggregates UROIIIS intracellular homeostasis and congenital erythropoietic porphyria UROIIIS intracellular concentration is altered in C73R-UROIIIS Quantitative roadmap of the pathogenic mutations that are affected by impaired homeostasis In vitro kinetic stability measures correlate with UROIIIS intracellular steady-state concentration for the congenital eryt... UROIIIS homeostasis and proteasomal degradation UROIIIS proteostasis restoration by proteasomal inhibition in animal models Ciclopirox as a pharmacological chaperone for congenital erythropoietic porphyria Pharmacological chaperones Ciclopirox and congenital erythropoietic porphyria Toward a modulation of the heme biosynthetic pathway Acknowledgments References