Table of Contents
Introduction to the Book 1
Long-Lived Proteins Are Ubiquitous 1
Aging 1
Autoimmunity 2
Age-Related Diseases 3
Our Lenses in the Vanguard 3
Brain and Memory 4
1 Long-Lived Cells and Long-Lived Proteins in the Human Body 5Roger J.W. Truscott
1.1 What Constitutes a Long-Lived Cell and a Long-Lived Protein? 5
1.2 Aim of the Chapter 6
1.3 Aging 6
1.4 Location of LLPs Within the Body 7
1.4.1 ECM and Tissue Function 7
1.5 Extracellular LLPs 7
1.5.1 Several ECM Components Are Long Lived 7
1.5.1.1 Elastin 7
1.5.1.2 Structural Glycoproteins and Proteoglycans 8
1.5.1.3 Collagens 8
1.6 Intracellular LLPs and LLCs 10
1.6.1 LLCs and LLPs in the Organs of the Body 10
1.7 Organs and Tissues that Contain LLCs or LLPs 11
1.7.1 Long-Lived Cells 11
1.7.1.1 Eye 11
1.7.1.2 Oocytes 14
1.7.1.3 Kidneys 15
1.7.1.4 Adipose Tissue 15
1.7.1.5 Brain 15
1.7.1.6 Heart 17
1.7.1.7 Lung 17
1.7.1.8 Skeleton 18
1.7.1.9 Teeth 18
1.7.1.10 Hair 18
1.7.1.11 Joints 19
1.7.1.12 Pancreas 19
1.7.1.13 Liver 20
1.7.1.14 Intestine 20
1.7.1.15 Dividing Cells and LLPs 21
1.7.2 Sensory Tissues 21
1.7.2.1 Hearing 21
1.7.2.2 Smell 21
1.8 Protein Changes and DNA Changes with Age 21
1.9 Processes Responsible for the Breakdown of LLPs 22
1.10 Oxidation: Methionine Sulfoxide Reductases and the Glutathione System 23
1.11 Consequences of LLP Decomposition 24
1.11.1 Protein Modification and Cellular Processing 24
1.11.2 Lifelong Proteins and the Consequences 24
1.12 LLPs and Age-Related Disorders 25
1.12.1 Modified LLPs Acting as Novel Antigens: Autoimmune Diseases 25
1.12.2 Defects in Cytosol/Nuclear Communication 25
1.12.3 Defects in Nuclear Transcription 26
1.12.4 Breakdown of Abundant Macromolecules 26
1.12.5 Elastin 26
1.12.6 Collagen 26
1.13 Neurological Diseases Where LLPs May be Implicated 27
1.13.1 Multiple Sclerosis 27
1.13.2 Motor Neuron Disease (MND)/Amyotrophic Lateral Sclerosis (ALS) 27
1.13.3 Alzheimer Disease (AD) 27
1.14 Aging DNA and LLPs 28
1.15 How Can the Role of LLPs in Aging and Disease Be Investigated? What Can Be Done 28
1.15.1 Heterogeneity of Aged LLPs: A Large Hurdle to Overcome 29
1.16 We Will Not Live Forever 29
1.16.1 LLP Degradation and Tissue Function: Is There a Threshold for Decay? 30
1.16.2 Lifelong Proteins May Degrade at Similar Rates 30
1.16.3 Decay in Tissue Function with Age and Its Effect on Fitness, Health, and Mortality 32
1.16.4 LLPs and Life Span 32
1.16.5 Heart 32
1.16.6 Lung 33
1.16.7 Nerves and Brain 33
1.17 Conclusion 33
Acknowledgments 33
References 33
2 Imaging Mass Spectrometry of Long-Lived Proteins 43Kevin L. Schey
2.1 Introduction 43
2.2 Imaging Mass Spectrometry Methods 44
2.2.1 General Considerations 44
2.2.2 MALDI-IMS 44
2.2.3 Desorption Electrospray Ionization (DESI)-IMS 46
2.2.4 Secondary Ion Mass Spectrometry (SIMS)-IMS 46
2.2.5 Other IMS Methods 46
2.3 Protein Identification 47
2.4 LLPs in the Body 48
2.4.1 Lens 48
2.4.2 Optic Nerve 51
2.4.3 Retina 52
2.4.4 Brain and CNS 52
2.4.5 Cartilage 53
2.5 Long-Lived Cells and Structures 53
2.6 Future Directions 54
References 54
3 Eye Lens Crystallins: Remarkable Long-Lived Proteins 59Aidan B. Grosas and John A. Carver
3.1 Introduction 59
3.2 Eye Lens and Its Transparency 59
3.3 Lens Crystallin Proteins 61
3.3.1 α-Crystallins 61
3.3.2 β- and γ-Crystallins 63
3.4 Congenital, Early Onset, and Age-Related Cataract 65
3.5 Protein Aggregation and Disease, Particularly Cataract 71
3.5.1 Protein Unfolding and Aggregation and Molecular Chaperones 71
3.5.2 Amyloid Fibril and Amorphous Protein Aggregates 73
3.5.3 Diseases Associated with Protein Aggregation 74
3.5.4 Crystallin Aggregation and Cataract 75
3.6 Concluding Comments 77
References 78
4 Spontaneous Breakdown of Long-Lived Proteins in Aging and Their Implications in Disease 97Michael G. Friedrich
4.1 Introduction 97
4.2 LLPs Are Found Throughout the Body 98
4.3 Spontaneous Modifications of Aging 99
4.3.1 Deamidation, Racemization, and Isomerization 99
4.3.2 Cross-linking 101
4.3.3 Truncation 102
4.3.4 Age, Disease, and Spontaneous PTMs: General Considerations 103
4.4 LLPs and Onset of Disease: Is Correlation the Only Answer? 105
4.4.1 Eye 106
4.4.1.1 Lens and Age-Related Nuclear Cataract 106
4.4.1.2 Retina, Vitreous Humor, and Sclera 108
4.4.2 Central Nervous System 108
4.4.2.1 Multiple Sclerosis 109
4.4.2.2 Alzheimer’s Disease 109
4.4.2.3 Parkinson’s Disease 110
4.4.2.4 Amyotrophic Lateral Sclerosis/Motor Neuron Disease 110
4.4.2.5 Systemic Lupus Erythematosus 111
4.4.3 Extracellular Matrix Proteins 111
4.4.3.1 Articular Cartilage, Intervertebral Disc, and Osteoarthritis 112
4.4.3.2 Circulatory System 112
4.4.3.3 Respiratory System 112
4.4.4 Digestive System 112
4.4.4.1 Diabetes 113
4.5 Spontaneous Modifications: Detrimental or Beneficial? 113
4.5.1 NGR Motifs 113
4.5.2 Bcl-xL 113
4.6 Protein Turnover Slows with Age 113
4.7 Potential Treatment of Diseases Initiated by LLPs 114
4.8 Future Outlook 114
Acknowledgments 115
References 115
5 Modifications of Long-Lived Proteins that Affect Protein Solubility 127Larry L. David
5.1 Introduction 127
5.2 Insoluble Protein Definition 128
5.3 Insolubilization Due to Disulfide Bonding 128
5.3.1 Disulfide Bonding Is Strongly Correlated with Age-Related Cataracts 128
5.3.2 Levels of Disulfide Bonding at Individual Cysteines in Cataractous Lenses 129
5.3.3 Identity of Individual Disulfide Cross-links in Crystallins of Aged Lenses 129
5.4 Insolubilization Due to Nondisulfide Cross-links 130
5.4.1 Cross-links Due to Dehydroalanine Formation 130
5.4.2 Cross-links Due to C-Terminal Anhydrides 130
5.5 Insolublization Due to Protein Fragmentation 131
5.5.1 Introduction: Protein Hydrolysis and Insolubilization 131
5.5.2 Proteolysis as a Driver of Protein Insolublization in Animal Lenses 131
5.5.3 Nonenzymatic Hydrolysis as a Driver of Protein Insolublization in Human Lenses 131
5.6 Insolublization Due to Deamidation, Isomerization, and Racemization 132
5.7 In vitro Studies of How PTMs Alter Protein Structure and Solubility 133
5.7.1 In vitro Studies of Disulfide Bonding 133
5.7.2 In Vitro Studies of Deamidation 135
5.8 Proteomics Methods to Detect Post-translation Modifications Contributing to Protein Insolublization 135
5.8.1 Crystallins as Ideal Proteins to Detect Age-Related PTMs 135
5.8.2 Two-Dimensional Liquid Chromatography/Mass Spectrometry to Detect PTMs 136
5.8.3 Searches for Known PTMs 136
5.8.4 Searches for Unknown PTMs 137
5.8.5 Identifying Disulfide Cross-links 138
5.8.6 Identifying Deamidation Sites 139
5.8.7 Identifying Isomerization Sites 142
5.8.8 Identifying Racemization Sites 143
5.8.9 Peptide Standards to Study Deamidation, Isomerization, and Racemization 145
5.9 Future PTM Studies of Long-Lived Proteins 145
5.10 Concluding Remarks 148
Acknowledgments 150
References 150
6 Degradation of Long-Lived Proteins as a Cause of Autoimmune Diseases 159Roger J.W. Truscott
6.1 Introduction 159
6.1.1 Background 159
6.1.2 Autoimmunity: Long-Lived Proteins and Long-Lived Cells 159
6.1.3 Focus of this Chapter 159
6.2 Long-Lived Cells Are Widespread in the Body 160
6.3 Long-Lived Proteins Are Present in Many Tissues 160
6.4 Long-Lived Proteins Decompose Over Time 161
6.5 Defenses Against LLP Decomposition 162
6.5.1 Rebuilding Degraded Asp and Asn Sites Within a Protein 162
6.5.2 Oxidation-Related Modification Repair Enzymes and Antioxidants 163
6.6 Consequences of Long-Lived Protein Decomposition 163
6.7 Individual Autoimmune Diseases 165
6.7.1 Pancreas 165
6.7.2 Nerves 165
6.7.3 Stomach 166
6.7.4 Blood Vessels 166
6.7.5 Gastrointestinal Tract 166
6.7.6 Liver 166
6.7.7 Thyroid Gland 166
6.7.8 Adrenal Gland 166
6.7.9 Joints 167
6.7.10 Multiple Sites 167
6.7.11 Skin 167
6.7.12 Moisture-Secreting Glands 167
6.7.13 Blood 167
6.7.14 Muscles 168
6.7.15 Heart 168
6.8 Person-to-Person Variability in Breakdown of LLPs: Multiple Sclerosis 168
6.8.1 Why Do Not All Adults Develop Autoimmune Disorders? 168
6.8.2 Widespread LLPs and Modulation of an Immune Response 169
6.9 Conclusions and Future Research 169
Acknowledgments 170
References 170
7 How Isomerization and Epimerization in Long-Lived Proteins Affect Lysosomal Degradation and ProteostasisRyan R. Julian 175
7.1 Proteostasis 175
7.2 Invisible Modifications 176
7.3 Repair 179
7.4 Identification 180
7.5 Protein Turnover 180
7.6 Mechanistic Considerations 181
7.7 Prevention 182
7.8 Conclusion 184
Acknowledgments 184
References 184
8 The Maillard Reaction: Protein Modification by Ascorbic Acid 189Vincent M. Monnier, David R. Sell, Grant Hom, Shiyuan Dong, Benlian Wang and Xingjun Fan
8.1 Introduction 189
8.2 Ascorbic Acid Homeostasis in the Lens: A Dual Sword 190
8.3 Ascorbic Acid as a Source of Age-Related Damage to the Lens 190
8.4 Chemical Pathways of Ascorbic Acid Degradation In Vitro and the Human Lens 191
8.5 Advanced Glycation End Products that have been Detected in the Human Lens 192
8.6 Glucose vs. Ascorbic Acid as a Source of Advanced Glycation End Products in the Lens 193
8.7 Ascorbic Acid as a Major Source of Oxoaldehydes in Lens and Brain 195
8.8 Significance of Advanced Glycation/Ascorbylation Products in the Lens and Brain 196
8.9 Conclusions 197
Acknowledgments 197
References 197
Index 203
