Handbook of Neurochemistry and Molecular Neurobiology. Neural Protein Metabolism and Function

Cover Page......Page 1
Half-Title......Page 2
Inside Cover......Page 3
Copyright Page......Page 4
Table of Contents......Page 5
Preface......Page 7
Contibutors......Page 8
1. Regulation of Protein Metabolism......Page 11
1 Introduction......Page 13
Formation of the 48S Complex......Page 14
Scanning and Assembly of the 80S Ribosome......Page 15
Cis-Acting Elements......Page 16
2.2.2 Termination Factors......Page 17
3.1 General Translational Control......Page 18
3.1.2 eIF2B Phosphorylation......Page 19
3.1.4 eIF4E Levels and Phosphorylation......Page 20
3.1.6 Translational Regulation by Other Initiation Factors......Page 21
3.2.1 Control at 5'-Oligopyrimidine Tract......Page 22
3.2.3 Upstream Open Reading Frames in the 5'-UTR: Reinitiation......Page 23
3.2.4 Control by Cis-Acting Elements Activated by Trans-Acting Factors......Page 24
4.2 Experimental Models of Cerebral Ischemia......Page 25
5.1 Ischemic Period......Page 26
5.2.1 Initiation Factors......Page 27
5.3.1 Initiation Factors and Protein Kinases......Page 29
5.3.2 eIF4G and Calpain Activation......Page 30
5.4 Translation Control in Delayed Neuronal Death......Page 31
5.4.1 Control of Protein Expression: GluR2......Page 32
5.5.1 Improvement of Initiation at Early Reperfusion......Page 33
References......Page 34
2. Cell Adhesion Molecules of the Immunoglobulin Superfamily in the Nervous System......Page 44
1.2 Restrictions in Protein Types and Species......Page 52
1.4 The Immunoglobulin Superfamily......Page 53
2.3 Expression......Page 54
2.6 Homophilic Interactions......Page 56
3.2 Gene......Page 58
3.6 Homophilic Interactions......Page 59
3.7.1 Extracellular Binding Partners......Page 60
3.8 Function......Page 61
4.1 Introduction......Page 62
4.2.3 Isoforms and Protein Structure......Page 63
Intracellular Binding Partners......Page 65
4.2.7 Function......Page 66
4.3.5 Homophilic Interactions......Page 67
5.3 Expression......Page 68
6.1 Introduction......Page 69
6.4 Isoforms and Protein Structure......Page 71
6.7.2 Intracellular Binding Partners......Page 72
6.8 Signaling......Page 73
6.9 Function......Page 74
7.2 Genes......Page 75
7.5 Posttranslational Modifications......Page 77
7.6 Nectin-Nectin Interactions......Page 78
7.8 Signaling......Page 79
8.1 Introduction......Page 80
8.2 Genes......Page 81
8.3 Expression......Page 82
8.5 Posttranslational Modifications......Page 83
8.7.1 Extracellular Binding Partners......Page 84
8.9 Functions......Page 85
9.2 Genes......Page 86
9.3 Expression......Page 87
9.6 Interactions Within the IgLON Family......Page 88
10.1 Introduction......Page 89
10.3 Expression......Page 90
10.7.1 Extracellular Binding Partners......Page 91
11.2 Genes......Page 92
11.4 Isoforms and Protein Structure......Page 93
11.8 Function......Page 94
12.2 Genes......Page 95
12.7 Heterophilic Binding Partners......Page 96
13.2 Gene......Page 97
13.4 Isoforms and Protein Structure......Page 98
13.6 Homophilic Interactions......Page 99
13.7.1 Extracellular Binding Partners......Page 100
13.8 Signaling......Page 102
13.9 Functions......Page 103
14.2 Gene......Page 104
14.6 Homophilic Interactions......Page 105
15.1 Introduction......Page 106
15.4 Isoforms and Primary Protein Structure......Page 107
15.7.1 Extracellular Binding Partners......Page 108
15.9 Functions......Page 109
16.2.2 Expression......Page 110
16.2.6 Heterophilic Binding Partners......Page 111
16.3.2 Expression......Page 112
16.3.8 Function......Page 113
17.1 Introduction......Page 114
17.2.2 Expression......Page 115
Extracellular Heterophilic Binding Partners......Page 116
17.2.7 Signaling......Page 118
17.3.3 Isoforms and Protein Structure......Page 119
17.4.3 Isoforms and Protein Structure......Page 120
17.5.2 Expression......Page 121
18.1 Introduction......Page 122
18.3 Expression......Page 123
18.6 Homophilic Interactions......Page 124
19.3 Isoforms and Protein Structure......Page 125
20.1 IGSF9......Page 127
20.4 TMEM25......Page 129
References......Page 130
3. Neurosecretory Protein Trafficking and Dense-Core Granule Biogenesis in Neuroendocrine Cells......Page 161
1 Introduction......Page 162
2.1 Sorting Signals in Neuropeptides and BDNF......Page 163
3 Trafficking of Proneuropeptide-Processing Proteases to Secretory Granules......Page 165
4.1 Role of Cholesterol in Secretory Granule Biogenesis......Page 169
4.2 Granulogenic Proteins: Assembly Factors......Page 170
4.3 Proteins Regulating DCG Biogenesis......Page 171
References......Page 172
4. Protein Synthesis at Synaptic Sites on Dendrites......Page 176
1 Introduction......Page 177
2 Form Implies Function: Morphology of Protein Synthetic Machinery at Synapses......Page 178
3 The Spine as a Protein Synthetic Compartment: Spatial Constraints Due to Size......Page 179
4 Documentation of Local Protein Synthesis in Dendrites......Page 180
6 What mRNAs Are Present in Dendrites/What Proteins Are Synthesized Locally at Synapses?......Page 181
6.2 In Situ Hybridization Analyses......Page 182
6.3 Isolation and Amplification of mRNA from Neurites of Neurons Growing in Culture......Page 186
7 Local Synthesis of Components of Multimolecular Signaling Complexes: Is There a Cotranslational Assembly?......Page 187
8.2 Cis-Acting Sequences That Identify mRNA for Dendritic Transport......Page 188
8.3 Dendrite-Specific RNA Transport......Page 189
9 Regulation of Translation of Dendritic mRNAs......Page 190
9.2 Translational Repression of Dendritic mRNAs While They Are in Transit......Page 191
9.3 The Fragile-X/BC1 Connection......Page 192
9.5 Regulation of Translation by Synaptic Signals......Page 193
10 Protein Synthesis in Axons......Page 194
10.1 Protein Synthesis in Growing Axons and Growth Cones......Page 195
11 Degradation of Dendritic mRNAs and Locally Synthesized Proteins......Page 196
References......Page 197
5. Emerging Functions of the "Ca2+ Buffers" Parvalbumin, Calbindin D-28k and Calretinin in the Brain......Page 203
1 Introduction......Page 204
2 Buffering vs Sensor Function of CaBPs......Page 205
3.1 Intracellular Concentration......Page 206
3.2 Metal-Binding Affinities......Page 207
3.5 Models Used to Investigate the Role of Synthetic Ca2+ Buffers and CaBPs......Page 210
4.1 PV......Page 211
4.2 CB......Page 212
4.3 CR......Page 213
5.1 PV Knockout Mice......Page 214
5.2 CB Knockout- and CB Antisense Mice......Page 215
5.3 CR Knockout Mice......Page 217
6 Alterations in CaBP Expression and Relation to Brain Pathologies......Page 218
6.2 Correlation vs Cause vs Secondary Adaptive Changes......Page 219
6.3 The  "Ca2+ Homeostasome"......Page 220
Acknowledgments......Page 221
References......Page 222
6. Actin, Actin-binding Proteins and Myosins in Nervous System......Page 228
2.2.1 Differential Function of Actin Isoforms......Page 230
2.3.2 Polarity of F-Actin and Treadmilling......Page 231
3.1.1 Gelsolin Superfamily......Page 233
3.2.1 Profilin......Page 234
3.2.2 Thymosin ß......Page 235
3.4.1 Fascin......Page 236
3.5.1 Tropomyosin......Page 238
3.5.3 Drebrin......Page 239
4.2.2 Differential Function of Myosin II Isoforms......Page 240
4.4 Myosin V......Page 241
4.5.5 Myosin X......Page 242
References......Page 243
7. Transglutaminase......Page 248
2 Reactions Catalyzed by TGases......Page 249
4 General Physiological Roles of the TGases......Page 252
6.1 CAG-Expansion Diseases......Page 254
6.2 Alzheimer's Disease......Page 257
7 TGases as Potential Therapeutic Targets in Neurodegenerative Diseases......Page 258
References......Page 259
8. Protein Alterations in Mental Retardation......Page 264
1.3 Diagnosis......Page 266
2.1.2 Creatine Defects......Page 267
2.1.5 HADII......Page 268
2.1.10 Congenital Disorders of Glycosylation......Page 269
2.2.2 Renpenning Syndrome......Page 270
2.2.6 West Syndrome/Partington Syndrome/Aristaless-Related Homeobox......Page 271
2.4.1 GDP Dissociation Inhibitor 1......Page 272
2.4.5 Rho Guanine Nucleotide Exchange Factor 6......Page 273
2.5.1 X-Linked Mental Retardation 34......Page 274
2.5.6 Thyroid-Stimulating Hormone Receptor......Page 275
2.6.2 Mowat-Wilson Syndrome......Page 276
3 Newer Approaches to Identify Altered Proteins in MR......Page 277
3.1 Array Comparative Genomic Hybridization......Page 278
3.3 cDNA Array......Page 279
3.4 Oligonucleotide Arrays......Page 280
3.5 Proteomics......Page 281
References......Page 282
9. Protein Sulfation......Page 288
1 Introduction......Page 289
2 Sulfation Pathways......Page 291
3 The Human Sulfotransferase Complement......Page 292
5.2 Sulfated Glycans in Chronic Inflammation......Page 296
5.3 Endothelial Sulfotransferases......Page 297
5.5 Other Immunologically Important Sulfotopes......Page 298
6.3 Endosulfatases Involved in HS Remodeling......Page 299
7 Sulfation in Regulation of Hormone Half-Life......Page 300
8.1 Sulfated Glycolipids in Myelin Structure and Function......Page 301
8.2 Chondroitin Sulfate in CNS Injury......Page 302
References......Page 303
10. Protein Folding......Page 308
1.1 Physical Forces and Principles Underlying Protein Folding and Structure......Page 310
2 The Protein-Folding Problem......Page 311
3 Folding Mechanisms and Kinetics......Page 313
4.1 The Structure of the Molten Globule......Page 315
4.2 The Role of the Molten Globule in Folding......Page 316
5.1 All-Atom Models......Page 317
6 Free-Energy Landscapes of Proteins......Page 318
7.1 Backbone Isomerization......Page 320
7.2 Formation of Disulfide Bridges......Page 322
8 Transition States on the Folding Pathway......Page 323
9.1 Multidomain Proteins......Page 325
9.2 Multi-Subunit Proteins......Page 326
10 Protein Folding in the Cell......Page 327
10.1 The Hsp70 Family......Page 328
10.2 The Folding Cage of Chaperonins (Hsp60 Family)......Page 329
10.6 Chaperones and Neurodegenerative Diseases......Page 330
11.2 The Structure and Morphology of Amyloid Fibrils......Page 332
11.4 Amyloid Formation of Globular Proteins......Page 333
11.5 Physicochemical and Sequence Determinants of Amyloid Formation......Page 334
12.2 Real-Time NMR Spectroscopy......Page 335
12.4 High-Pressure NMR Spectroscopy......Page 336
13 Conclusions......Page 337
References......Page 338
11. Neurodegenerative Dementias Involving Aberrant Protein Aggregation......Page 349
2.1 Amyloidopathy......Page 350
2.2 Tauopathy......Page 351
2.4 Polyglutamine Diseases......Page 353
3 Mechanism of UPS Proteolysis and Neurodegenerative Dementia......Page 354
4 Relationship Between UPS and Endoplasmic Reticulum......Page 355
5 Conclusion......Page 356
References......Page 357
12. Polyglutamine Diseases......Page 358
2 Clinical Features of Polyglutamine Diseases......Page 359
3.3 Ataxin-1......Page 360
3.7 DRPLA Product (Atrophin-1)......Page 361
4.1 Processing of Polyglutamine Proteins......Page 362
4.3 Ubiquitination of Polyglutamine Protein......Page 363
4.6 Aggregation Sites in the Cell......Page 364
5.2 ER Stress......Page 365
6 Frontier of Therapeutic Approaches......Page 366
6.2 Cross-Linking Inhibition......Page 367
6.5 RNAi......Page 368
References......Page 369
13. The Proteasome, Protein Aggregation, and Neurodegeneration......Page 373
2 Biochemistry of the Proteasome......Page 375
2.1.1 Structure......Page 376
2.1.4 Inhibitors......Page 377
2.3.1 11S Regulator (PA28)......Page 378
2.4.2 The 19S Regulatory Complex......Page 379
2.5 Hybrid Proteasomes......Page 380
2.6.3 E2: Ubiquitin-Conjugating Enzyme......Page 382
2.6.5 Targeting of Substrates for Ubiquitination and Degradation......Page 383
2.7 Ubiquitin-Independent Proteolysis......Page 384
3.1 a-Synuclein......Page 385
3.1.1 a-Synuclein Degradation......Page 386
3.1.2 a-Synuclein and the Proteasome......Page 387
3.2 Parkin......Page 388
3.3 a-Synuclein and Parkin......Page 390
3.4 Studies on the Proteasome in Parkinson's Disease......Page 391
4 Protein Aggregation and the Proteasome......Page 392
4.1 The Aggresome......Page 393
4.2.1 Colocalization of Inclusions and Components of the Ubiquitin-Proteasome System......Page 395
Huntingtin......Page 396
4.3 The Role of the Proteasome in Protein Aggregation and Inclusion Formation......Page 397
4.4 Evidence That Aggregate Formation Is Responsible for Cellular Pathology......Page 398
4.5 Evidence That Inclusions May Be Cytoprotective......Page 399
4.6 Are Polyglutamine-Expanded Proteins Proteasome Substrates or Proteasome Inhibitors?......Page 400
5 Conclusion......Page 401
References......Page 402
14. Serine Proteases......Page 411
1 The Structure and Function of Serine Proteases......Page 412
2.1 Activity and Specificity of Hemostatic Serine Proteases......Page 415
2.3 Characterization of the Protease-Activated Receptors......Page 416
2.4 Localization of Hemostatic Serine Proteases and PARs......Page 417
2.5 The Role of Plasma Serine Proteases in the Physiology and Pathology of the CNS......Page 418
3.1 Nomenclature, Genomic Localization, and Structure of Kallikrein Genes......Page 420
3.2 Regulation of Expression and Alternative Splicing......Page 421
3.4 Biological Roles of Kallikreins and Their Association with Diseases......Page 427
3.5 Potential Roles of Kallikreins in the CNS......Page 428
3.6 Kallikreins in Alzheimer's Disease......Page 429
4.1 Chromosomal Localization and Transcription of Human Trypsin Genes......Page 430
4.2 Regional Distribution of Human Trypsin 4 mRNA and Protein in the Brain......Page 431
4.3 Structural and Biochemical Characterization of Human Trypsin 4......Page 433
4.4 On the Potential Role of Human Trypsin 4 in Physiological or Pathological Processes in the CNS......Page 435
References......Page 437
15. Calpain as a Target for Prevention of Neuronal Death in Injuries and Diseases of the Central Nervous System......Page 446
1 Introduction......Page 448
2.1.1 Glutamate Receptor Channels......Page 449
2.1.2 Ligand-Gated Ca2+ Channels......Page 450
2.3 Ca2+ Extrusion and Sequestration......Page 451
3.1.1 Necrotic and Apoptotic Neuronal Death......Page 452
3.2.1 Ca2+ Accumulation, Calpain Activation, and Neuronal Death......Page 453
3.3.2 Calpain Activation and Calpain Inhibition......Page 454
4.1.1 Role of Calpain in Neurodegeneration......Page 455
4.2.2 Calpain Activation in Motoneuron Death and Calpain Inhibition......Page 456
4.3.2 Oxidative Stress Leading to Calpain Activation......Page 457
4.5 Parkinson's Disease......Page 458
4.6.1 Multiple Mechanisms of Pathogenesis......Page 459
Acknowledgments......Page 460
References......Page 461
16. Secretase Processing of Amyloid Precursor Protein (APP) and Neurodegeneration......Page 469
1 Introduction......Page 470
1.1 The Amyloid Hypothesis......Page 471
1.2 APP Heterogeneity......Page 473
2.1 Characterization......Page 475
2.2 Domain Structure and Therapeutic Implications......Page 477
2.4 Alternative a-Secretases......Page 478
3 ß-Secretases (BACE-1 and -2)......Page 479
3.1.1 Characterization......Page 480
3.3 Pharmacology......Page 481
4.2 Stepwise Assembly and Maturation of Complexes......Page 483
4.3 Isolation of gamma-SC......Page 485
4.4 Specificity......Page 487
4.4.1 AICD and Cell Signaling......Page 489
4.5 gamma-SC Inhibition......Page 490
5.1 Presenilins (PS1, PS2)......Page 493
5.3 Aph-1......Page 495
6 Alternative Proteases as Secretases......Page 496
References......Page 497
17. The Biology of Caspases in Central Nervous System Trauma......Page 515
1 Apoptosis Versus Programmed Cell Death......Page 516
2.2 Inflammatory Caspases......Page 517
2.3 Caspases of the Death Cascade......Page 519
3.1 The Mitochondrial (Intrinsic) Pathway of Apoptotic Cell Death......Page 520
3.2 Regulation of Apoptosis by Bcl-2 Family Members at Mitochondria......Page 521
3.3 The Death Receptor (Extrinsic) Pathway of Apoptotic Cell Death......Page 525
3.4 The ER (Intrinsic) Pathway of Apoptotic Cell Death......Page 526
3.5 Additional Pathways of Caspase Activation......Page 528
4 Substrate Cleavage by Activated Caspases......Page 529
7.1 Introduction......Page 530
7.3 Traumatic Brain Injury......Page 531
7.4 Traumatic Spinal Cord Injury......Page 532
8.1 Competitive Inhibitors......Page 533
8.2 Anti-Apoptotic Genes......Page 534
9 Conclusion......Page 535
References......Page 536
18. Microglial Proteases......Page 551
1 Introduction......Page 552
2.2 Degradation of Extracellular Matrix Proteins......Page 553
2.3 Intracellular Degradation of Aß Peptides......Page 555
3.1 Degradation of ECM Proteins......Page 556
3.3 Activation of Microglia......Page 557
5.1 Degradation of ECM Proteins......Page 558
6 Calpains......Page 559
7 Caspases......Page 560
References......Page 561
19. MMPs and Other Matrix-Degrading Metalloproteinases in Neurological Disease......Page 565
1 Extracellular Matrix in the CNS and Matrix-Degrading Proteinases......Page 566
2.1 Matrix Metalloproteinases......Page 567
2.1.2 Gelatinases......Page 568
2.1.6 Other MMPs......Page 569
2.3 A Disintegrin and Metalloproteinase with Thrombospondin Motifs......Page 570
3 Matrix Metalloproteinases in Neurological Disease......Page 572
3.1 Multiple Sclerosis......Page 574
3.2 Cerebral Ischemia and Opening of the Blood-Brain Barrier......Page 575
3.3 Glioma Invasion and Angiogenesis......Page 576
3.4.1 Alzheimer's Disease......Page 578
3.4.2 HIV Dementia......Page 579
References......Page 581
20. Protease Inhibitors and their Involvement in Neurological Disorders......Page 591
2 Nonspecific Protease Inhibitors: a-Macroglobulins......Page 592
2.1 a2-M in the Nervous System and Neurological Disorders......Page 593
3.1 Serine Protease Inhibitors......Page 594
3.2 Cysteine Protease Inhibitors......Page 599
Alzheimer's Disease and Aging......Page 601
Brain Tumors......Page 602
Alzheimer's Disease......Page 603
3.3.1 TIMPs in the Nervous System and Neurological Disorders......Page 604
3.3.4 Vascular Dementia......Page 605
References......Page 606
21. Neuropeptidases......Page 625
2.1 Neuropeptides in Degenerative Diseases......Page 626
2.2 Neuropeptides in Cerebrospinal Fluid......Page 627
2.4 Neuropeptide Degradation in Neurological Diseases......Page 628
2.6 Endopeptidases in Neurological Diseases......Page 629
4 Enkephalin-Processing Enzymes......Page 630
4.3 Carboxypeptidase H/E......Page 632
5 Enkephalin-Degrading Enzymes......Page 633
5.2 Angiotensin-Converting Enzyme......Page 634
5.3.2 Puromycin-Sensitive Aminopeptidase......Page 635
PSA Gene......Page 636
PSA in Development......Page 637
5.3.3 Neuron-Specific Aminopeptidases......Page 638
NAP1 During Neuron Growth......Page 639
NAP1 Is a Putative Synaptic Enzyme......Page 640
6.2 N-Acetylated a-Linked Acidic Dipeptidase (NAALADase)......Page 641
7.2 Synthetic Anti-Aminopeptidase......Page 642
7.5 Inactivation of Arg0-Met-Enk......Page 643
References......Page 644
22. Ubiquitination and Proteasomal Protein Degradation in Neurons......Page 652
2 The Ubiquitin-Proteasome System......Page 653
3 Ubiquitination and Deubiquitination in Neurons......Page 654
4 Subunit Composition and Regulatory Functions of the Neuronal Proteasome......Page 656
5 The Crucial Role of the UPS in Neurological Disease......Page 657
6 Conclusions......Page 658
References......Page 659
23. Protease Activity in the Aging Brain......Page 662
1 Proteolytic Systems in the Brain......Page 663
3 Age-Related Changes in the Ubiquitin-Proteasome System......Page 664
4 The Garbage Catastrophe Model......Page 665
5 Genetic Models of Age-Related Proteolytic Deficit......Page 666
Summary......Page 668
References......Page 669
24. From Concept to Potential Therapeutics: Neuroprotective Peptides......Page 672
1.1 Neuroprotective Proteins and Peptides: SNV, ADNF, and ADNP......Page 673
1.1.2 The Discovery of ADNF and ADNP......Page 674
ADNF-Derived Peptides: Structure-Activity Relations......Page 675
1.1.4 ADNP......Page 676
2.2.3 Fetal Alcohol Syndrome Mouse Model......Page 677
2.2.7 Memory in Middle-Aged Rat Models......Page 680
3.1 Mechanism of Action of NAP......Page 681
3.2 Mechanism of Action of ADNF-9/SAL......Page 682
References......Page 683
Index......Page 688