Protein Misfolding Diseases E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Wiley Series in Protein and Peptide Science
• Sprache: Englisch

Seitenzahl: 2027

Veröffentlichungsjahr: 2010

Beschreibung

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.

Leseprobe

CONTENTS

Contributors

Foreword

Preface

Acknowledgments

Introduction to the Wiley Series on Protein and Peptide Science

Part I: Principles of Protein Misfolding

Chapter 1: Why Proteins Misfold

Introduction

Why Proteins Misfold in vitro

The Determinants of Protein Aggregation from Largely or Partially Unfolded States

Why Proteins Misfold in Vivo

Conclusions

References

Chapter 2: Endoplasmic Reticulum Stress and Oxidative Stress: Mechanisms and Link to Disease

Introduction

Protein Folding and Quality Control in the ER

Upr Signaling

Perk Phosphorylates eIF2α to Attenuate mRNA Translation

Atf6-Mediated Transcriptional Activation Requires Regulated Intramembrane Proteolysis

BiP is a Master Regulator of UPR Sensor Activation

ER and Oxidative Protein Folding

Er Stress and Oxidative Stress: Implications in Clinical Disease

Future Perspectives

References

Chapter 3: Role of Molecular Chaperones in Protein Folding

Introduction

Protein Flux through the Chaperone Network

Ribosome-Binding Chaperones

The Hsp70 System

Chaperonins

Medical Significance of Chaperones

References

Chapter 4: Kinetic Models for Protein Misfolding and Association

Introduction

Principles

Examples

Beyond Linear Polymerization

Other Special Considerations

References

Chapter 5: Toxicity in Amyloid Diseases

Introduction

Biological Surfaces can be Key Triggers of Amyloid Precursor Production, Aggregation, and Toxicity

Amyloid Aggregates Display Generic Toxicity

Shared Biochemical Modifications in Cells Exposed to Toxic Aggregates

Cellular Context

Final Considerations

References

Chapter 6: Autophagy: an Alternative Degradation Mechanism for Misfolded Proteins

Introduction

Autophagy

Autophagy and Protein Conformation Disorders

Concluding Remarks

References

Chapter 7: Role of Posttranslational Modifications in Amyloid Formation

Introduction

Aberrant Enzymatically Catalyzed Posttranslational Modifications can Play a Critical Role in Protein Aggregation Diseases

Proteins are Subjected to a Wide Range of Nonenzymatic Modifications in vitro and in Vivo

Concluding Remarks

References

Chapter 8: Unraveling Molecular Mechanisms and Structures of Self-Perpetuating Prions

Introduction

Known and Potential Fungal Prions

Prion Generation and Propagation

Prion Amyloid Structure

Prion Strains

Prion Species Barriers

Conclusions and Perspectives

References

Chapter 9: Caenorhabditis Elegans as a Model System to Study the Biology of Protein Aggregation and Toxicity

Introduction

C. Elegans Models for Neurodegenerative Diseases of Protein Folding

Polyglutamine Protein Aggregation Dynamics

Genetic Screens for Modifiers of Disease-Related Phenotypes

Small-Molecule Drug Screens

Stress, Protein Homeostasis, and Aging

References

Chapter 10: Using Drosophila to Reveal Insight into Protein-Misfolding Diseases

Drosophila as a Model System for Human Neurodegenerative Disease

Features of Protein Misfolding Diseases

Modeling Protein Misfolding Diseases in the Fly

Insight from Modifier Screens

From Genes to the Foundation for Therapeutic Compounds

Summary and the Future

References

Chapter 11: Animal Models to Study the Biology of Amyloid-β Protein Misfolding in Alzheimer Disease

Introduction

Assaying the Effects on Memory of Aβ in Transgenic Mice

Differentiating between the Roles of Aβ and Amyloid Plaques in Memory Loss

Zeroing in on Aβ*56, a Soluble Aβ Assembly in the Brain that Impairs Memory

Conclusions

References

Part II: Protein Misfolding Disease: Gain-of-Function and Loss-of-Function Diseases

Chapter 12: Alzheimer Disease: Protein Misfolding, Model Systems, and Experimental Therapeutics

Introduction

Clinical and Laboratory Features of Cases of Mci and Ad

Neuropathology and Biochemistry

Genetics: Familial Ad and Influences of Risk Factors

App, Aplp, and Secretases

Transgenic Models of Aβ Amyloidosis and Tauopathies

Results of Targeting of Genes Encoding Amyloidogenic Secretases

Experimental Manipulations and Potential Therapeutic Strategies

Conclusions

References

Chapter 13: Prion Disease Therapy: Trials and Tribulations

Introduction

Immune-Based Therapies

Chemical-Based Therapies and Prophylaxis

Targeting Prpc

Combination Therapy

Human Treatments

Conclusions

References

Chapter 14: Misfolding and Aggregation in Huntington Disease and other Expanded Polyglutamine Repeat Diseases

Introduction

Case for a Toxic Misfolded Monomer

Aggregation of Simple Polyq Sequences

Altered Aggregation of PolyQ with Flanking Sequences

Role of the Cellular Environment

Toxicity Mechanisms Related to Protein Misfolding

Therapeutic Possibilities

Note Added in Proof

References

Chapter 15: Systemic Amyloidoses

Introduction

Systemic vs. Neurodegenerative Amyloidosis: Protein Secretion and Site of Deposition

Sources of Protein and Secretion

Causes of Amyloid Deposition

Systemic Deposition: Tissue Targeting

Mechanisms of Organ Damage

References

Chapter 16: Hemodialysis-Related Amyloidosis

Introduction

β2M Structure and Function in Vivo

Constituents of β2M Amyloid Deposits

Mechanism of Fibril Formation of β2M

β2M Fibril Structure

Identifying Regions Involved in Aggregation

Clues as to the Identity of the Amyloid Precursor State

Role of Cu2+

Implications for Therapy

References

Chapter 17: Copper–Zinc Superoxide Dismutase, Its Copper Chaperone, and Familial Amyotrophic Lateral Sclerosis

Structural Properties of Copper–Zinc Superoxide Dismutase

Genetics and Models of Sod1-Linked Fals

Aggregation of Mutant Sod1 in Fals

Copper Chaperone for Sod1 and Sod1 Maturation

Alternate Model for Ccs Action

Immature Pathogenic Sod1 and Toxicity

Therapeutics

Conclusions

References

Chapter 18: Alpha-1-Antitrypsin Deficiency

Introduction

Lung Disease

Liver Disease

Structural Pathobiology of α1-Antitrypsin Deficiency

Cellular Pathobiology of α1-Antitrypsin Deficiency

Current and Potential Therapeutic Strategies

References

Chapter 19: Folding Biology of Cystic Fibrosis: a Consortium-Based Approach to Disease

Introduction

Cystic Fibrosis and the Cystic Fibrosis Conductance Regulator: Genetics and Clinical Manifestations Defining the Depth of the Problem

Translocation into the Er Membrane

Co-Translational Folding of Cftr

Recognition and Degradation of Mutant Cftr

Cftr Structure

Trafficking to the Cell Surface

Stability and Trafficking At the Cell Surface

Current Efforts and Future Opportunities to Correct Cftr Folding: the Way Forward

References

Chapter 20: Thiopurine S-Methyltransferase Pharmacogenomics: Protein Misfolding, Aggregation, and Degradation

Introduction

Tpmt Pharmacogenetics: Discovery and Clinical Importance

Tpmt Pharmacogenomics: Clinical Consequences

Tpmt Pharmacogenomics: Molecular Mechanisms

Tpmt Pharmacogenomics: Mechanisms of Degradation

Tpmt Pharmacogenomics: Autophagy

Conclusions

References

Chapter 21: Gaucher Disease

Introduction

Glucocerebrosidase

Protein Folding and Gaucher Disease

N370S Mutation

L444P and G202R Mutations

Current Therapies

Future Therapies

Conclusions

References

Chapter 22: Cataract as a Protein-Aggregation Disease

Introduction

Properties of Cataracts

Etiology of Cataracts in Humans

Structure and Function of the Lens Crystallins

Folding, Stability, and Unfolding of Crystallins

In vitro Crystallin Aggregation Pathways and Chaperone Activities

Covalent Modifications of Crystallins

Mechanistic Models for Cataract Formation

Cytoskeleton Proteins of Lens Cells

Membrane Proteins of Lens Cells

Prospects for Progress

References

Chapter 23: Islet Amyloid Polypeptide

Introduction

Normal Physiological Role of Iapp

Synthesis and Processing of Iapp

Not All Species Form Islet Amyloid

Aromatic Interactions and Amyloid Formation By Iapp and other Polypeptides

Structural Models of the Iapp Amyloid Protofilament

Kinetics of in vitro Amyloid Formation By Iapp

Islet Amyloid Formation in Type 2 Diabetes and in Islet Cell Transplantation

Iapp Membrane Interactions

Helical Intermediates and Amyloid Formation By Iapp: a General Phenomenon?

Inhibitors of Iapp Amyloid Formation

Role of Iapp Analogs in the Treatment of Type 1 Diabetes

References

Part III: Role of Accessory Molecules and Risk Factors

Chapter 24: Role of Metals in Alzheimer Disease

Introduction

Role of Amyloid Beta in Ad

Current Therapeutic Approaches to Ad

References

Chapter 25: Why Study the Role of Heparan Sulfate in In Vivo Amyloidogenesis?

Introduction

What Do I Know About Heparan Sulfate and Its Role in Amyloidogenesis in Vivo?

What Would I Like to Know About the Role of Heparan Sulfate in In Vivo Amyloidogenesis?

References

Chapter 26: Serum Amyloid P Component

Introduction

Structure of Amyloid Fibers

Structure of Sap

References

Chapter 27: Role of Oxidatively Stressed Lipids in Amyloid Formation and Toxicity

Lipids and Alzheimer Disease

Oxidative Stress and Lipids

Aβ Proteins and Oxidative Stress

Lipids and the Thermodynamics of Fibril Formation

The Proteomics of Oxidative Stress in Ad

Lipoprotein E and Oxidative Stress

Mouse Models of Ad and Oxidative Stress

Vicious Cycles Involving Lipids and Ad

Summary

References

Chapter 28: Role of Oxidative Stress in Protein Misfolding and/or Amyloid Formation

Introduction

Lipid-Derived Aldehydes: Chemical and Biological Origins

Lipid Aldehydes and Protein Misfolding or Amyloidogenesis

Conclusions

References

Chapter 29: Aging and Aggregation-Mediated Proteotoxicity

Introduction

The Regulation of Life Span and Aging

IIS and Toxic Protein Aggregation

Biological Counter-Proteotoxicity Activities

Influences on the Age of Onset of Neurodegeneration

References

Part Iv: Medical Aspects of Disease: Diagnosis and Current Therapies

Chapter 30: Imaging of Misfolded Proteins

Introduction

Why Imaging?

Early Detection

Histology

Labeling of Ad Pathology in Vivo

In Vivo Imaging

Brain Pathology

Conclusions

References

Chapter 31: Diagnosis of Systemic Amyloid Diseases

Introduction

Congo Red Stain

Biopsy Diagnosis of Amyloid

Distinguishing Between Localized and Systemic Amyloidosis

Classification of Amyloidosis on Biopsy Tissue Specimens

Radionuclide Imaging of Amyloid Deposits

Sap Component Scan

Echocardiographic Assessment of Cardiac Amyloidosis

Magnetic Resonance Imaging Assessment of Amyloidosis

Conclusions

References

Chapter 32: Identification of Biomarkers for Diagnosis of Amyloid Diseases: Quantitative Free Light-Chain Assays

Introduction

Free Light-Chain Quantitation

Diagnostic Sensitivity for Identification of Monoclonal Flc

Monitoring Disease Activity

References

Chapter 33: Real-Time Observation of Amyloid-β Fibril Growth By Total Internal Reflection Fluorescence Microscopy

Introduction

Total Internal Reflection Fluorescence Microscopy

Real-Time Observation of Aβ(1–40) Fibril Growth

Effects of Various Surfaces on the Growth of Aβ Fibrils

Formation of Aβ Spherulitic Structures

Conclusions

References

Chapter 34: Current and Future Therapies for Alzheimer Disease

Introduction

Mouse Models of Ad

App and Aβ-Specific Therapeutic Targets

Tau-Specific Therapeutic Targets

Targeting Pleitropic Factors that Modulate Ad Neuropathology

Future Challenges in Development of Clinically Relevant Therapies

Summary

Note Added in Proof

References

Chapter 35: Current Therapies for Light-Chain Amyloidosis

Introduction

Assigning a Prognostic Category to Patients With Systemic Al

Treatment of Systemic Al

Treating Localized Amyloidosis

References

Chapter 36: Familial and Senile Amyloidosis Caused By Transthyretin

Introduction

Transthyretin-Associated Amyloidosis

Senile Systemic Amyloidosis

References

Chapter 37: Identifying Targets in α-Synuclein Metabolism to Treat Parkinson Disease and Related Disorders

Parkinson Disease

Related Synucleinopathy Disorders of the Brain

Alpha-Synuclein: a Protein Prone to Misfolding

Alpha-Synuclein Metabolism as the Focus of Research

De Novo Protein Synthesis: Transcription and Translation

Modulators of Snca Gene Transcription

Modulating Snca Mrna Translation

Degradation of Neural α-Synuclein

Concluding Remarks

References

Chapter 38: Emerging Molecular Targets in the Therapy of Dialysis-Related Amyloidosis

Introduction

Reduction of Circulating β2M

Identification of β2M Interactors: Molecular Overview

Identification of β2M Interactors: Learning from Rational Mutant Design

Modification of the Fibrillogenic Environment

Conclusions

References

Chapter 39: Familial Amyloidosis Caused By Lysozyme

Introduction

Lysozyme Amyloidosis: Clinical Manifestations and Current Therapies

Insight into the Molecular Mechanism of Lysozyme Fibril Formation from Examination of ex vivo Fibrils

Insight into the Molecular Mechanism of Lysozyme Fibril Formation from Biochemical and Biophysical Characterization of the Variant Proteins

Mechanism of Lysozyme Amyloid Fibril Formation

Inhibition of in vitro Lysozyme Amyloid Fibril Formation

Conclusions and Perspectives

References

Chapter 40: Therapeutic Prospects for Polyglutamine Disease

Introduction

Reducing Polyglutamine Protein Expression

Targeting Polyglutamine Protein for Degradation

Histone Deacetylase Inhibition

Caspase Inhibition

Neurotrophic Factors

Transglutaminase Inhibition

Disease-Specific Treatment

References

Part V: Approaches for New and Emerging Therapies

Chapter 41: Chemistry and Biology of Amyloid Inhibition

Introduction

Macromolecular Inhibitors of Amyloid Formation

Antibodies and Immunotherapy

Apolipoprotein E

Small-Molecule Inhibitors of Amyloidosis

Mechanisms of Action

Summary

References

Chapter 42: Immunotherapy in Secondary and Light-Chain Amyloidosis

Introduction

Immunotherapy for Amyloid Diseases

Antigens for Immunotherapy of Al and Aa

Preclinical Immunotherapy for Aa and Al Amyloidosis

Prospects and Problems With Immunotherapy for Peripheral Amyloidoses

References

Chapter 43: Anti-Misfolding and Anti-Fibrillization Therapies for Protein Misfolding Disorders

Introduction

Amyloid-Binding Proteins as Natural Inhibitors of Protein Misfolding and Aggregation

Antibodies and Vaccines to Prevent and Remove Misfolded Aggregates

Small-Molecule Inhibitors of Amyloid Formation

Peptide Inhibitors of Protein Misfolding

References

Chapter 44: Therapies Aimed At Controlling Gene Expression, Including Up-Regulating a Chaperone or Down-Regulating an Amyloidogenic Protein

Introduction

Molecular Chaperones: Function in Folding and Misfolding

Regulation of the Hsr

Pharmacological Induction of the Hsr

Prospects

Down-Regulation of Amyloidogenic Protein Expression: Gene Silencing By Rna Interference as a Potential Therapeutic Approach for Protein Misfolding Diseases

Principles of Rnai

Rnai Therapy: Risks and Challenges

Conclusions

References

Chapter 45: Understanding and Ameliorating the Ttr Amyloidoses

Overview

Introduction to Amyloid Diseases

Introduction to Transthyretin

Mechanism of Ttr Amyloidogenesis

Ttr Amyloidogenesis Occurs By a Downhill Polymerization

Current Understanding of the Etiology of the Ttr Amyloid Diseases

Influence of the Cellular Proteostasis Network on Ttr Amyloidogenesis

Disease-Associated Ttr Mutants are Thermodynamically Less Stable Than Wild-Type Ttr

Natural Suppression of a Ttr-Associated Amyloid Disease: Strong Support for the Amyloid Hypothesis

A Surgical Form of Gene Therapy is Currently Utilized to Treat Fap

Selective Small-Molecule Binding to Tetrameric Ttr Imposes Kinetic Stabilization on the Tetramer: a Chemotherapeutic Strategy for the Ttr Amyloidoses

Ttr Kinetic Stabilizers Must Bind Selectively to Ttr Over the Remainder of the Proteome to be Effective

References

Index

WILEY SERIES ON PROTEIN AND PEPTIDE SCIENCE

VLADIMIR N. UVERSKY, Series Editor

Metalloproteomics · Eugene A. Permyakov

Protein Misfolding Diseases: Current and Emerging Principles and Therapies · Edited by Marina Ramirez-Alvarado, Jeffery W. Kelly, and Christopher M. Dobson

Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Protein misfolding diseases : current and emerging principles and therapies / [edited by] Marina Ramirez-Alvarado, Jeffery W. Kelly, Christopher M. Dobson.

p.; cm.

Includes bibliographical references and index.

ISBN 978-0-471-79928-3 (cloth)

1. Proteins—Metabolism—Disorders. 2. Protein folding. 3. Amyloidosis. I. Ramirez-Alvarado, Marina. II. Kelly, Jeffery W. III. Dobson, C. M. (Christopher M.) [DNLM:

1. Amyloidosis—etiology. 2. Protein Folding. 3. Amyloidosis—diagnosis. 4. Amyloidosis—therapy. 5. Senile Plaques. WD 205.5.A6 P967 2010]

RC632.P7P673 2010

616.3′995—dc22

2009027972

CONTRIBUTORS

Andisheh Abedini, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York

John Ancsin, Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada; Syl and Molly Apps Research Center, Kingston General Hospital, Kingston, Ontario, Canada

Alison E. Ashcroft, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK

Karen H. Ashe, Department of Neurology, University of Minnesota, Minneapolis, Minnesota

Paul H. Axelsen, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

William E. Balch, Department of Cell Biology and Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, California

Tadato Ban, Institute for Protein Research, Osaka University, Osaka, Japan

Vittorio Bellotti, Dipartimento di Biochimica, Università di Pavia, Pavia, Italy

Merrill D. Benson, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana

Anat Ben-Zvi, Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois

Julide Bilen, Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia

Grant E. Boldt, Department of Biochemistry, The Scripps–Oxford Laboratory, University of Oxford, Oxford, UK

Nancy M. Bonini, Department of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania

David R. Borchelt, Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida

Ineke Braakman, Department of Cellular Protein Chemistry, University of Utrecht, Utrecht, The Netherlands

Jeff Brodsky, Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania

Ashley I. Bush, Mental Health Research Institute of Victoria, Parkville, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts

Joel N. Buxbaum, Departments of Molecular and Experimental Medicine and Molecular Integrative Neuroscience, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California

Silvia Campioni, Laboratorium für Physikalische Chemie, ETH Zürich, Switzerland

Byron Caughey, Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana

Paramita Chakrabarty, Department of Neuroscience, College of Medicine, Mayo Clinic Florida, Jacksonville, Florida

Kausik Chakraborty, Department of Cellular Biochemistry, Max-Planck Institute of Biochemistry, Martinsried, Germany

Fabrizio Chiti, Dipartimento di Scienze Biochimiche, Università di Firenze, Firenze, Italy

Sungwook Choi, Departments of Chemistry and Molecular and Experimental Medicine, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California

Ehud Cohen, The Institute for Medical Research Israel–Canada, The Hebrew University Medical School, Jerusalem, Israel

Ana Maria Cuervo, Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York

Valerie Cullen, LINK Medicine, Cambridge, Massachusetts

Pritam Das, Department of Neuroscience, College of Medicine, Mayo Clinic Florida, Jacksonville, Florida

Andrew Dillin, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla California

Angela Dispenzieri, Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota

Mireille Dumoulin, Centre d’Ingénierie des Protéines, Institut de Chimie, Université de Liège, Liège, Belgium

Tim Edmunds, Therapeutic Protein Research, Genzyme Corporation, Framingham, Massachusetts

R. John Ellis, Department of Biological Sciences, University of Warwick, Coventry, UK

Gennaro Esposito, Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy

Frank A. Ferrone, Department of Physics, Drexel University, Philadelphia, Pennsylvania

Mark A. Findeis, Satori Pharmaceuticals Incorporated, Cambridge, Massachusetts

Kenneth H. Fischbeck, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Raymond Frizzell, Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Florian Georgescauld, Department of Cellular Biochemistry, Max-Planck Institute of Biochemistry, Martinsreid, Germany

Morie A. Gertz, Department of Medicine, Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota

Todd E. Golde, Department of Neuroscience, College of Medicine, Mayo Clinic Florida, Jacksonville, Florida

Yuji Goto, Institute for Protein Research, Osaka University, Osaka, Japan

William Guggino, Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Ruchi Gupta, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York

P. John Hart, Department of Biochemistry and the X-ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas

F. Ulrich Hartl, Department of Cellular Biochemistry, Max-Planck Institute of Biochemistry, Martinsreid, Germany

Manajit Hayer-Hartl, Department of Cellular Biochemistry, Max-Planck Institute of Biochemistry, Martinsreid, Germany

Steven M. Johnson, Departments of Chemistry and Molecular and Experimental Medicine, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California

Celeste Karch, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri

Jerry A. Katzmann, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

Randal J. Kaufman, Departments of Biological Chemistry and Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan

Jeffery W. Kelly, Departments of Chemistry and Molecular and Experimental Medicine, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California

Elise A. Kikis, Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois

Jonathan A. King, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts

Robert Kisilevsky, Department of Pathology and Molecular Medicine and Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada; Syl and Molly Apps Research Center, Kingston General Hospital, Kingston, Ontario, Canada

Simon Kolstoe, Centre for Amyloidosis and Acute Phase Proteins, University College London Medical School, London, UK

Hiroaki Komatsu, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Maria Kon, Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York

Shaji Kumar, Division of Hematology, Mayo Clinic, Rochester, Minnesota

Michael K. Lee, Department of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Harry Levine, III, Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky

Fang Li, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota

Tong Li, Department of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Susan Lindquist, Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Cambridge, Massachusetts

David A. Lomas, Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

Gregor P. Lotz, Gladstone Institute of Neurological Disease, University of California, San Francisco, California

Gergely L. Lukacs, Department of Physiology, McGill University, Montreal, Quebec, Canada

Jyoti D. Malhotra, Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan

Peter Marek, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York

Zane Martin, Departments of Neurology, Neuroscience and Cell Biology, and Biochemistry and Molecular Biology, George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas

Fanling Meng, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York

Elodie Monsellier, Dipartimento di Scienze Biochimiche, Università di Firenze, Firenze, Italy

Richard I. Morimoto, Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois

Paul J. Muchowski, Gladstone Institute of Neurological Disease, and Departments of Biochemistry and Biophysics, and Neurology, University of California, San Francisco, California

Johan F. Paulsson, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

Christopher Penland, Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California

Maria Pennuto, Department of Neuroscience, Italian Institute of Technology, Genoa, Italy

David H. Perlmutter, Departments of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

Harvey Pollard, Department of Anatomy, Physiology and Genetics, School of Medicine, University of the Health Sciences, Bethesda, Maryland

Evan T. Powers, Department of Chemistry, The Scripps Research Institute, La Jolla, California

Donald L. Price, Department of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Mercedes Prudencio, Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida

Sheena E. Radford, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK

Daniel P. Raleigh, Department of Chemistry, Graduate Program in Biochemistry and Structural Biology, State University of New York at Stony Brook, Stony Brook, New York

Marina Ramirez-Alvarado, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota

Natàlia Reixach, Departments of Chemistry and Molecular and Experimental Medicine, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California

Blaine R. Roberts, Mental Health Research Institute of Victoria, Parkville, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

Alena V. Savonenko, Department of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Johanna C. Scheinost, Department of Biochemistry, The Scripps–Oxford Laboratory, University of Oxford, Oxford, UK

Michael G. Schlossmacher, Division of Neuroscience, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Valerie L. Sim, Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada

William Skach, Department of Biochemistry and Molecular Biology, Oregon Health and Sciences University, Portland, Oregon

David P. Smith, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK

Eric Sorscher, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Claudio Soto, Departments of Neurology, Neuroscience and Cell Biology, and Biochemistry and Molecular Biology, George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas

Massimo Stefani, Department of Biochemical Sciences and Research Centre on the Molecular Basis of Neurodegeneration, University of Florence, Florence, Italy

Humeyra Taskent, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York

Peter M. Tessier, Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York

Philip Thomas, Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas

Julianna Tomlinson, Division of Neuroscience, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Sylvia Tracz, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York

Jonathan Wall, Human Immunology and Cancer Program, Preclinical and Diagnostic Molecular Imaging Laboratory, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee

Yongting Wang, Department of Neuroscience, Shanghai Jiao Tong University, Shanghai, P.R. China

Richard M. Weinshilboum, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota

Paul Wentworth, Jr., Department of Biochemistry, The Scripps–Oxford Laboratory, University of Oxford, Oxford, UK; Department of Chemistry, The Scripps Research Institute, La Jolla, California

Ronald Wetzel, Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Duane D. Winkler, Department of Biochemistry and the X-ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas

R. Luke Wiseman, Departments of Chemistry and Molecular and Experimental Medicine, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California

Daniel P. Witter, Department of Biochemistry, The Scripps–Oxford Laboratory, University of Oxford, Oxford, UK

Philip C. Wong, Department of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Steve Wood, Centre for Amyloidosis and Acute Phase Proteins, University College London Medical School, London, UK

Steven R. Zeldenrust, Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota

FOREWORD

The English philosopher Cyril Joad was famous for responding to any question by saying “It all depends on what you mean by. . . .” He was often lampooned for this habit, but, of course, he was absolutely correct. Definitions are important in science because science is basically a set of ideas about how the world works, and these ideas are expressed in words. So it is not a semantic quibble to insist on defining terms—in fact, I would argue that, in the last analysis, science is semantics.

So what is protein misfolding, and why is it important? There is no generally agreed definition of this term in the literature. The prefix mis indicates that something is wrong, and what I want to suggest is that some definitions of the term misfolding do not reflect this. In fact, misfolding seems to mean different things to different people. So I want to suggest, firstly, that our definition of misfolding should be clarified, and second, that there appears to be remarkably little evidence that misfolding per se is a serious problem for the cell—the problem is misassembly, not misfolding. To explain why I make these suggestions, I need to remind you of the definitions of the terms folding and assembly, which are used commonly in relation to proteins.

Folding is defined as the collapse of an elongated primary translation product into a stable compact monomer, whereas assembly is the binding of monomers to one another to produce a biologically functional oligomer. The distinction between folding and assembly is not absolute but quantitative, because in both processes there are changes in the conformation of polypeptide chains, but these changes are usually much smaller during assembly than during folding. Notice that while folding is defined entirely in structural terms, the definition of assembly contains a biological criterion in addition to a chemical one. The word is used to distinguish these oligomers from nonfunctional assemblies, and to make this explicit, nonfunctional oligomers are called , or more commonly, .