Protein folding and misfolding: neurodegenerative diseases

1. Structural Disorder and Its Connection with Misfolding Diseases; Veronika Csizmok and Peter Tompa. 1. 1 The Concept of Protein Disorder. 1. 2 Biophysical and Bioinformatics Characterization of Disorder. 1. 2. 1 Biophysical Techniques 1. 2. 2 Bioinformatics Techniques. 1. 3 Disorder in Vivo, the Effect of Crowding? 1. 4 Disorder and Aggregation. 1. 5 Disorder in Neurodegenerative Diseases. 1. 6 Physiological Prions. 1. 7 Structural Transition to Amyloid: Partially Folded Intermediates. 1. 8 The Structure of Amyloid: Cross-Beta Models and Flexibility. 1. 9 Conclusions. References. 2 Intrinsic Disorder in Proteins Associated with Neurodegenerative Diseases Vladimir N. Uversky. 2. 1 Neurodegenerative Diseases as Proteinopathies. 2. 2 Introducing Intrinsically Disordered Proteins. 2. 2. 1 Concept. 2. 2. 2 Experimental Techniques for IDP Detection. 2. 2. 3 Sequence Peculiarities of IDPs and Predictors of Intrinsic Disorder. 2. 2. 4 Abundance of IDPs and their Functions. 2. 3Abundance of IDPs in Neurodegenerative Diseases. Evidence from the Bioinformatics Analyses. 2. 4 Intrinsic Disorder in Proteins Associated with -Protein and Alzheimer s Disease. 2. 4. 2 Neurodegenerative Diseases. 2. 4. 1 Amyloid Tau Protein in Alzheimer s Disease and Other Tauopathies. 2. 4. 3 Prion Protein and Prion Diseases. 2. 4. 4 Synucleins - and Synuclein and Synucleinopathies. 2. 4. 5 Parkinson s Disease and Dementia with Lewy Bodies. 2. 4. 6 Polyglutamine Repeat Diseases and Huntingtin, Ataxin-1, Ataxin-3, androgen Receptor and Atrophin-1. 2. 4. 7 Abri Peptide and Familial British Dementia. 2. 4. 8 Adan in Familial Danish Dementia. 2. 4. 9 Glial Fibrillary Acidic Protein and Alexander and Alpers Disease. 2. 4. 11DNA Disease. 2. 4. 10 Mitochondrial DNA Polymerase Excision Repair Protein ERCC-6 and Cockayne Syndrome. 2. 4. 12 Survival of Motor Neurons Protein and Spinal Muscular Atrophy. 2. 5 Concluding Remarks: Another Illustration of the D2 Concept. References. 3 Dynamic Role of Ubiquitination in the Management of MisfoldedProteins Associated with Neurodegenerative Diseases. Esther S. P. Wong, Jeanne M. M. Tan and Kah-Leong Lim. 3. 1 Protein Misfolding and the Ubiquitin-Proteasome System. 3. 2 Protein Misfolding, UPS Disruption and Neurodegeneration. 3. 3 Diversity of Ubiquitin Modifications. 3. 4 Non-Proteolytic Ubiquitination and Protein Inclusions Biogenesis. 3. 5 Aggresomes Formation and Clearance. 3. 6 K63-Linked Polyubiquitination A Novel Cargo Recognition Signal For Autophagic Degradation. 3. 7 A Model of Inclusion Biogenesis and Clearance. 3. 8 E2/E3 Pairs Triage officers? . 3. 9 Conclusions. References. 4. Protein Misfolding and Axonal Protection in Neurodegenerative Diseases. Haruhisa Inoue, Takayuki Kondo and Ryosuke Takahashi. 4. 1 Neuronal Dysfunction in Neurodegeneration Are Reversible Process. 4. 2 Neuronal Dysfunction Is Not Treatable by Anti-Cell Death Therapy. 4. 3 Morphological Aspects of Neuronal Dysfunction Caused by Protein Aggregation/Misfolding in Human Neurodegenerative Disorder. 4. 4 Protein Misfolding and Axonal Degeneration in Experimental Animal Models. 4. 5 Therapeutic approaches to treat neuronal dysfunction by axonal protection. 4. 5. 1 Axonal regeneration. 4. 5. 2 Anti-Wallerian Degeneration. 4. 5. 3 Autophagy Enhancement. 4. 5. 4 Stabilization of Microtubules. 4. 6 Concluding remarks. References. 5. Endoplasmic Reticulum Stress in Neurodegeneration Jeroen J. M. Hoozemans and Wiep Scheper. 5. 1Introduction. 5. 2 Protein Quality Control in the Endoplasmic Reticulum. 5. 2. 2 Triage: ERAD. 5. 2. 3 Degradation: Ubiquitin Proteasome System and Autophagy. 5. 2. 4 Stress Response: The Unfolded Protein Response. 5. 2. 5 ER-Stress-Induced Cell Death. 5. 3. ER Stress in Neurodegenerative Disorders. 5. 3. 1 Alzheimer s Disease. 5. 3. 2 Parkinson s Disease 5. 3. 3 Prion Disease. 5. 3. 4 Tauopathies. 5. 3. 5 Polyglutamine Diseases. 5. 3. 6 Amyotrophic Lateral Sclerosis. 5. 3. 7 White Matter Disorders. 5. 4 Conclusions . References. 6. Involvement of Alpha-2 Domain in Prion Protein Conformationally-InducedDiseases Luisa Ronga, Pasquale Palladino, Ettore Benedetti, Raffaele Ragone and Filomena Rossi. 5. 1. Conformational Diseases. 5. 2. Prion Biology. 5. 3. Approaches to TSE therapy: Anti-Prion Compounds. 5. 4. Immune Intervention. 5. 5. Prion Protein Structure. 5. 6. Determinants of Prpc Conversion: the N-Terminal Region. 5. 7. Determinants of Prpc Conversion: the C-Globular Domain. 5. 8. Prion-Metal Ion Binding. 5. 9. The a -2 Helix Domain: What Role? . 5. 10. Solution Structure of Prp[173-195] and Its Analogues. 5. 11. Metal Ion Titration. 5. 12. Anion-Induced Effects. 5. 13. Conclusions. References. 7 Synuclein Structure and Function in Parkinson' s Disease. David Eliezer. 7. 1 Background. 7. 1. 1 The Discovery of Synucleins. 7. 1. 2 Synuclein Mutations in Parkinson s Disease. 7. 1. 3 Synuclein in Lewy Bodies. 7. 1. 4 Synuclein Toxicity. 7. 1. 5 Synuclein Function. 7. 2 Free State Structure. 7. 2. 1 Residual Secondary Structure. 7. 2. 2 Role of Residual Structure in Aggregation. 7. 2. 3 Transient Long-Range Interactions. 7. 3 Fibril Structure. 7. 4 Lipid-Bound Structure. 7. 4. 1 A Role for Synuclein Function in Disease? . 7. 4. 2 Secondary Structure. 7. 4. 3 Topology. 7. 4. 4 Effects of Parkinson s Disease-Linked Mutations. 7. 5Synuclein. 7. 6 New Model for Synuclein Function. References. 8 Inhibition of a-Synuclein Aggregation by Antioxidants and Chaperones in Parkinson s Disease Jean-Christophe Rochet and Fang Liu. 8. 1 Introduction. 8. 2 Molecular Details of a-Synuclein Aggregation. 8. 2. 1 a-Synuclein Is a Natively Unfolded, Presynaptic Protein. 8. 2. 2 a-Synuclein Forms Fibrils and Protofibrils. 8. 2. 3 a-Synuclein Protofibrils Permeabilize Membranes. 8. 2. 4 a-Synuclein Self-Assembly Is Promoted by Membranes. 8. 2. 5 a-Synuclein Aggregates Disrupt Protein Clearance Mechanisms. 8. 2. 6 a-Synuclein Is Post-Translationally Modified in Parkinson s Disease. 8. 2. 7 a-Synuclein Self-Assembly Is Stimulated by Oxidative Modifications. 8. 2. 8 a-Synuclein Aggregation Is Modulated by Phosphorylation. 8. 2. 9 Summary (PartI). 8. 3 Inhibition of a-Synuclein Aggregation by Molecules with Antioxidant Activity. 8. 3. 1 Inhibition of a-Synuclein Aggregation by MsrA. 8. 3. 2 Inhibition of a-Synuclein Aggregation by Small-Molecule Antioxidants. 8. 3. 3 Summary (Part II). 8. 4 Inhibition of a-Synuclein Aggregation by Molecular Chaperones. 8. 4. 1 Inhibition of a-Synuclein Aggregation by Hsp70. 8. 4. 2 Inhibition of a-Synuclein Aggregation by aB-Crystallin and Hsp27. 8. 4. 3 Interaction Between a-Synuclein and Hsp90. 8. 4. 4 Inhibition of a-Synuclein Aggregation by TorsinA. 8. 4. 5 Inhibition of a-Synuclein Aggregation by DJ-1. 8. 4. 6 -Synucleinopathies Summary (Part III). 8. 5 Concluding remarks. References. 9 Novel Proteins in Christine Lund Petersen and Poul Henning Jensen. 9. 1 Introduction. 9. 2 The Synucleinopathies. 9. 3 -Synuclein Aggregation. 9. 4. 1 Synuclein. 9. 4 Proteins Involved in Brain-Specific Protein P25a/TPPP. 9. 4. 2 Tau. 9. 4. 3 Synphilin-1. 9. 4. 4 TAR-DNA-Binding Protein 43 (TDP-43). 9. 4. 5 Leucine-Rich Repeat Kinase 2 (LRRK2). 9. 4. 6 FK506-Binding Proteins. 9. 4. 7 Histones 9. 4. 8 Other -Synuclein Aggregation. 9. 5 Concluding Remarks. References. Proteins Involved in 10 TPPP/P25: A New Unstructured Protein Hallmarking Synucleinopathies Ferenc Orosz, Attila Lehotzky, Judit Olah Stb and Judit Ovádi. 10. 1 Occurrence of TPPP Proteins. 10. 2 Unfolded Structural Features of TPPP Proteins. 10. 2. 1 Prediction. 10. 2. 2 Experimental. 10. 3 Interacting Partners of TPPP/P25. 10. 4 TPPP Expression At Cell Level. 10. 4. 1 Structures and Effects in Living Cells. 10. 4. 2 Energy State. 10. 4. 3 Function. 10. 4. 4 Human Cell Model For Aggresome Development. 10. 5 TPPP/P25 in Brain Tissues. 10. 5. 1 Normal Brain. 10. 5. 2 Pathological Brain. 10. 6 Impact of Unfolded Structures On Physiological and Pathological Functions. References. 11 Tau protein in Alzheimer' s Disease and Other Tauopathic Neurodegenerative Diseases Jeff Kuret. 12 Protein-Base Neuropathology and Molecular Classification of Human Neurodegenerative Diseases Gabor G. Kovacsand Herbert Budka. 12. 1 Introduction. 12. 2 Classification of Neurodegenerative Disease: Basic Concepts. 12. 3 Proteins with Relevance For the Classification of Neurodegenerative Diseases. 12. 3. 1 Microtubule-Associated Protein Tau. 12. 3. 2 b -Amyloid. 12. 3. 3 a -Synuclein. 12. 3. 4 Prion Protein. 12. 3. 5 TAR-DNA-Binding Protein 43 (TDP-43). 12. 3. 6 a -Internexin. 12. 3. 7 Other Proteins. 12. 4 Morphological Types of Extra- and Intracellular Protein Deposits. 12. 4. 1 Extracellular Protein Deposition. 12. 4. 2 Intracellular Protein Deposition. 12. 5 Other Distinguishing Morphological Features. 12. 6 Synthesis: Classification of Neurodegenerative Diseases. 12. 7 Concluding Remarks. References. Index