Movement Disorders

The use of animal models is a key aspect of scientific research in numerous fields of medicine. Movement Disorders, Second Edition vigorously examines the important contributions and application of animal models to the understanding of human movement disorders, and serves as an essential resource for basic neuroscientists engaged in movement disorders research. Academic clinicians, translational researchers and basic scientists are brought together to connect experimental findings made in different animal models to the clinical features, pathophysiology and treatment of human movement disorders.

The book is divided into sections on Parkinson's disease, Huntington's disease, dystonia, tremor, paroxysmal movement disorders, ataxia, myoclonus, restless legs syndrome, drug-induced movement disorders, multiple system atrophy, progressive supranuclear palsy/corticobasal degeneration, and spasticity. This book serves as an essential resource for both clinicians interested in the science being generated with animal models and basic scientists studying the pathogenesis of particular movement disorders.

• Introduces the scientific foundations for modern movement disorders research
• Contributing authors are internationally known experts
• Completely revised with 20% new material
• Provides a comprehensive discussion of genetics for each type of movement disorder
• Covers Parkinson's disease, Huntington's disease, dystonia, tremors, and tics

General neurologists, neurologists with subspecialty interest in movement disorders, neuroscientists, rehabilitation physicians, psychiatrists, and academic veterinarians with an interest in animal models.

• Foreword
• Preface
• Section I. Scientific Foundations
  • Chapter 1. Taxonomy and Clinical Features of Movement Disorders
    • 1.1. Introduction
    • 1.2. Parkinson Disease
    • 1.3. Essential Tremor
    • 1.4. Huntington Disease and Other Choreiform Disorders
    • 1.5. Dystonia
    • 1.6. Wilson Disease
    • 1.7. Myoclonus
    • 1.8. Gilles de la Tourette Syndrome
    • 1.9. Drug-Induced Movement Disorders
    • 1.10. Hemiballism
    • 1.11. Summary
  • Chapter 2. Modeling Disorders of Movement
    • 2.1. Scientific Application of Animal Models
    • 2.2. Choice of the Appropriate Animal Model
    • 2.3. Experimental Approaches
    • 2.4. Disorder-Specific Animal Models
  • Chapter 3. New Transgenic Technologies
    • 3.1. Genome Modification
    • 3.2. Inducible Transgenes and Conditional Alleles
    • 3.3. Applications of Transgenic Technology and Transgene Design
    • 3.4. New Technologies: The Advent of Nucleases
    • 3.5. Avoiding Experimental Snares in Animal Model Research
    • 3.6. Future Prospects
  • Chapter 4. Assessment of Movement Disorders in Rodents
    • 4.1. Introduction
    • 4.2. Basic Concepts of Animal Modeling
    • 4.3. Specific Tests for Motor Abnormalities
    • 4.4. Global Strategies for Assessing Movement Disorders
    • 4.5. Suggested Test Batteries for Specific Movement Disorders
    • 4.6. Summary
  • Chapter 5. Drosophila
    • 5.1. Introduction: A Historical Perspective on Flies and Genetic Disease Research
    • 5.2. Basics of Genetic Analysis
    • 5.3. Genes, Genome, and Homologies
    • 5.4. Nervous System Organization
    • 5.5. Detecting Movement Abnormalities
    • 5.6. Genetic Tools of the Trade
    • 5.7. Applications of the Drosophila Model in Movement Disorder Research
    • 5.8. Prospects for the Future
  • Chapter 6. Use of Caenorhabditis elegans to Model Human Movement Disorders
    • 6.1. Caenorhabditis elegans: Why the Worm?
    • 6.2. Caenorhabditis elegans Web-Based Resources
    • 6.3. The C. elegans Nervous System
    • 6.4. Detection of Movement Abnormalities
    • 6.5. Tools of the Worm Trade
    • 6.6. As the Worm Turns: Application of C. elegans to Movement Disorders Research
    • 6.7. Drug Screening
    • 6.8. Concluding Remarks
  • Chapter 7. Zebrafish
    • 7.1. Introduction
    • 7.2. Why Zebrafish Models are Useful: Screens, In Vivo Imaging, and Genetic Tools
    • 7.3. Zebrafish Genes, Cells, and Circuits Relevant to Studying Human Motor System Diseases
    • 7.4. Zebrafish Genetic Methods: Knockouts and Transgenic Lines
    • 7.5. Neurobehavioral Testing in Zebrafish
    • 7.6. Chemical Screening
    • 7.7. Conclusions
  • Chapter 8. Techniques for Motor Assessment in Rodents
    • 8.1. Introduction
    • 8.2. Motor Coordination and Balance
    • 8.3. Locomotor Activity
    • 8.4. Fine Motor Skills
    • 8.5. Akinesia and Muscular Strength
    • 8.6. Conclusions
  • Chapter 9. Induced Pluripotent Stem Cells (iPSCs) to Study and Treat Movement Disorders
    • 9.1. Background
    • 9.2. Modeling Movement Disorders Using iPSCs
    • 9.3. Induced Pluripotent Stem Cells as a Platform for Cell Therapy and Drug Discovery
    • 9.4. Conclusions
  • Chapter 10. Neurophysiologic Assessment of Movement Disorders in Humans
    • 10.1. Introduction
    • 10.2. Assessment Methods
    • 10.3. Movement Disorders
    • 10.4. Recommendations and Conclusions
    • 10.5. Conclusion
  • Chapter 11. Neurophysiological and Optogenetic Assessment of Brain Networks Involved in Motor Control
    • 11.1. Deep Brain Stimulation (DBS) as a Therapeutic Option for Parkinson Disease (PD)
    • 11.2. Challenges and Opportunities in DBS Studies
    • 11.3. The Expanding Toolkit Optogenetic Technologies
    • 11.4. Experimental Optogenetic Technologies for Improving Existing DBS Practice
    • 11.5. Conclusions
  • Chapter 12. Functional Imaging to Study Movement Disorders
    • 12.1. Introduction
    • 12.2. Positron Emission Tomography
    • 12.3. Single-Photon Emission Computed Tomography
    • 12.4. Magnetic Resonance Imaging
    • 12.5. Concluding Remarks
  • Chapter 13. Human and Nonhuman Primate Neurophysiology to Understand the Pathophysiology of Movement Disorders
    • 13.1. Introduction to the Basal Ganglia
    • 13.2. Models of Basal Ganglia Function
    • 13.3. Neurophysiologic Studies of the Basal Ganglia in PD
    • 13.4. Dystonia
    • 13.5. Summary
• Section II. Parkinson Disease
  • Chapter 14. The Phenotypic Spectrum of Parkinson Disease
    • 14.1. Epidemiology of PD
    • 14.2. Genetics of PD
    • 14.3. Pathophysiology of PD
    • 14.4. Clinical Features of PD
    • 14.5. Summary
  • Chapter 15. Genetics and Molecular Biology of Parkinson Disease
    • 15.1. Introduction
    • 15.2. Genetic Contribution to Parkinson Disease
    • 15.3. Molecular Pathways in Parkinson Disease
  • Chapter 16. Genotype–Phenotype Correlations in Parkinson Disease
    • 16.1. Introduction
    • 16.2. Dominant PD Genes
    • 16.3. Recessive PD Genes
    • 16.4. Additional Genes
    • 16.5. Acid β-Glucosidase (GBA)
    • 16.6. Limitations in Our Present Knowledge on Genotype–Phenotype Correlations
    • 16.7. Subtypes of Parkinson Disease
  • Chapter 17. From Man to Mouse: The MPTP Model of Parkinson Disease
    • 17.1. Introduction
    • 17.2. MPTP
    • 17.3. Variations on the MPTP Mouse Model Theme
    • 17.4. Non-MPTP Models of PD
    • 17.5. Summary
  • Chapter 18. Rodent Models of Autosomal Dominant Parkinson Disease
    • 18.1. Introduction
    • 18.2. Models of Parkinson Disease
    • 18.3. SNCA
    • 18.4. LRRK2 (PARK8)
    • 18.5. UCHL1
    • 18.6. Vacuolar Protein Sorting 35
    • 18.7. Grb10-Interacting GYF Protein 2
    • 18.8. HTRA2
    • 18.9. Conclusions
  • Chapter 19. Rodent Models of Autosomal Recessive Parkinson Disease
    • 19.1. Autosomal Recessive PD
    • 19.2. PARKIN
    • 19.3. PINK1
    • 19.4. DJ-1
    • 19.5. Insights from Double and Triple Mutants
    • 19.6. Conclusions
  • Chapter 20. Drosophila Models of Parkinson Disease
    • 20.1. Introduction
    • 20.2. Modeling Parkinson Disease in Drosophila
    • 20.3. Concluding Remarks
  • Chapter 21. Primate Models of Complications Related to Parkinson Disease Treatment
    • 21.1. Introduction
    • 21.2. The Pathology of MPTP-Induced Parkinsonism
    • 21.3. Levodopa-Induced Motor Complications
    • 21.4. Successes, Failures, and Emerging Concepts on the Use of MPTP-NHPs in Translational Medicine
    • 21.5. Nonmotor Complications of Advancing PD
    • 21.6. Conclusion
  • Chapter 22. Rodent Models of Treatment-Related Complications in Parkinson Disease
    • 22.1. Introduction
    • 22.2. Overview of the Main Molecular and Biochemical Correlates of Dyskinesia in Rodent Models
    • 22.3. Challenges to Creating Rodent Models of Nonmotor Complications
    • 22.4. Tasks for Cognitive and Psychiatric Dysfunction in Rodent Models of PD
    • 22.5. Animal Models to Study Dopaminergic Modulation of ICDs
    • 22.6. Animal Models to Study Dopaminergic Modulation of Cognitive Deficits
    • 22.7. Concluding Remarks
  • Chapter 23. Methods and Models of the Nonmotor Symptoms of Parkinson Disease
    • 23.1. Introduction
    • 23.2. Anxiety
    • 23.3. Olfaction
    • 23.4. Gastrointestinal
    • 23.5. Sleep
    • 23.6. Depression
    • 23.7. Cognition
    • 23.8. Summary
• Section III. Dystonia
  • Chapter 24. Dystonia: Phenotypes and Genetics
    • 24.1. Introduction
    • 24.2. Clinical Features
    • 24.3. Primary Dystonia
    • 24.4. Dystonia-Plus
    • 24.5. Heredodegenerative Dystonia
    • 24.6. Dystonia in Association with Other Neurogenetic Disorders
    • 24.7. Conclusions
  • Chapter 25. Murine Models of Caytaxin Deficiency
    • 25.1. Phenotypic Characterization of the Genetically Dystonic Rat
    • 25.2. Response of the Genetically Dystonic Rat to Pharmacological Agents
    • 25.3. Neurochemical Analyses in the Genetically Dystonic Rat
    • 25.4. Motoric Effects of Cerebellar Lesions in the Genetically Dystonic Rat
    • 25.5. Olivocerebellar Neurophysiology in the Genetically Dystonic Rat
    • 25.6. Genetics
    • 25.7. Other Caytaxin Model Systems
    • 25.8. Caytaxin
    • 25.9. Relationship to Human Dystonia
  • Chapter 26. Animal Models of Focal Dystonia
    • 26.1. Introduction
    • 26.2. Spasmodic Torticollis
    • 26.3. Focal Hand Dystonia
    • 26.4. Benign Essential Blepharospasm
  • Chapter 27. Mouse Models of Dystonia
    • 27.1. Introduction
    • 27.2. Genetic Models of Dystonia
    • 27.3. Drug-Induced Models of Dystonia
    • 27.4. Summary and Conclusions
  • Chapter 28. Rodent Models of Autosomal Dominant Primary Dystonia
    • 28.1. Introduction
    • 28.2. DYT1 Dystonia
    • 28.3. Rodent Models of DYT11 Myoclonus-Dystonia
    • 28.4. Rodent Model of DYT12 Dystonia
    • 28.5. Rodent Model of DYT25 Dystonia
    • 28.6. Conclusions from Rodent Models of Autosomal Dominant Primary Dystonia
  • Chapter 29. Modeling Dystonia-Parkinsonism
    • 29.1. Rapid-Onset Dystonia-Parkinsonism (DYT12)
    • 29.2. The Na+/K+–ATpASE Pump
    • 29.3. Animal Models of Rapid-Onset Dystonia-Parkinsonism
    • 29.4. Alternating Hemiplegia of Childhood
    • 29.5. Other Types of Dystonia with Signs of Dystonia and Parkinsonism
    • 29.6. Conclusions
• Section IV. Huntington Disease
  • Chapter 30. Genetics of Huntington Disease (HD), HD-Like Disorders, and Other Choreiform Disorders
    • 30.1. Autosomal Dominant Choreas
    • 30.2. Autosomal Recessive Choreas
    • 30.3. X-Linked Choreas (MCLeod Syndrome)
    • 30.4. Conclusion
  • Chapter 31. Murine Models of HD
    • 31.1. Huntington Disease
    • 31.2. The Use of Mice to Study Disease
    • 31.3. Mouse Models of HD
    • 31.4. Recommendations on the Use of HD Mouse Models in Therapeutics and Preclinical Studies
    • 31.5. Conclusions
  • Chapter 32. Use of Genetically Engineered Mice to Study the Biology of Huntingtin
    • 32.1. Huntingtin Structure, Expression Pattern, and Protein Interactions
    • 32.2. Huntingtin Function during Embryonic Development
    • 32.3. Roles of Huntingtin in the Developing Brain
    • 32.4. Neuroprotective Functions of Huntingtin
    • 32.5. Roles of Huntingtin Structural Elements
    • 32.6. Effects of Huntingtin in Peripheral Organ Systems
    • 32.7. Conclusions
  • Chapter 33. Modeling Huntington Disease in Yeast and Invertebrates
    • 33.1. Introduction
    • 33.2. Modeling HD in Yeast
    • 33.3. Modeling HD in C. elegans
    • 33.4. Modeling HD in Drosophila melanogaster
    • 33.5. Conclusions and Future Directions
  • Chapter 34. HDL2 Mouse
    • 34.1. Introduction
    • 34.2. The Contribution of Expanded Polyglutamine to HDL2 Pathogenesis
    • 34.3. The Contribution of JPH3 Loss of Function to HDL2 Pathogenesis
    • 34.4. The Contribution of RNA Toxicity to HDL2 Pathogenesis
    • 34.5. Conclusions
  • Chapter 35. Analysis of Nonmotor Features in Murine Models of Huntington Disease
    • 35.1. Huntington Disease: The Importance of Nonmotor Disturbances
    • 35.2. Huntington Disease Mouse Models Used for the Analysis of Huntington Disease Nonmotor Phenotypes
    • 35.3. Depression and Anxiety in Huntington Disease Mouse Models
    • 35.4. Cognitive Impairment in Huntington Disease Mouse Models
    • 35.5. Metabolic Disturbances and Sleep Disturbances in Huntington Disease Mouse Models
    • 35.6. Confounding Effects
    • 35.7. Summary
• Section V. Tremor
  • Chapter 36. Essential Tremor
    • 36.1. Introduction
    • 36.2. Historical Perspective
    • 36.3. Epidemiology
    • 36.4. Clinical Features
    • 36.5. Treatment
    • 36.6. Pathophysiology and Pathology
    • 36.7. Genetics
  • Chapter 37. Use of the Harmaline and α1 Knockout Models to Identify Molecular Targets for Essential Tremor
    • 37.1. Harmaline Model
    • 37.2. The α1 KO Model
    • 37.3. Attempts to Identify Drug Targets for Tremor Suppression
    • 37.4. Survey of Other Potential Targets for ET Therapy
    • 37.5. Concluding Remarks
  • Chapter 38. Physiological and Behavioral Assessment of Tremor in Rodents
    • 38.1. Tremor in Human Neuropathologies
    • 38.2. Early Pharmacological Models of Tremor in Rodents: Cholinomimetics, Harmine, and Harmaline
    • 38.3. Tremulous Jaw Movements in Rats: A Model of Parkinsonian Resting Tremor
    • 38.4. Conclusions and Future Directions
  • Chapter 39. Mouse Models of the Fragile X Tremor/Ataxia Syndrome (FXTAS) and the Fragile X Premutation
    • 39.1. Introduction
    • 39.2. CGG Knockin Mouse Model of PM and FXTAS
    • 39.3. CGG KI Mouse Behavioral Analyses
    • 39.4. Future Directions
    • 39.5. Conclusions
• Section VI. Myoclonus
  • Chapter 40. Myoclonus: Classification, Clinical Features, and Genetics
    • 40.1. Introduction
    • 40.2. Physiologic Classification
    • 40.3. Clinical and Etiologic Classification
  • Chapter 41. Mouse Model of Unverricht-Lundborg Disease
    • 41.1. Introduction
    • 41.2. Cystatin B-Deficient Mouse
    • 41.3. Implications for Patient Care
  • Chapter 42. Post-Hypoxic Myoclonus in Rodents
    • 42.1. Historical Background
    • 42.2. Procedures for Induction of Post-hypoxic Myoclonus in Rats
    • 42.3. Behavioral Evaluation of Post-hypoxic Myoclonus in Rats
    • 42.4. Pharmacological Studies for Validation of the Animal Model
    • 42.5. Deficits in GABAergic and Serotonergic Activity in Post-hypoxic Myoclonus
    • 42.6. Neurodegeneration Revealed by Histology Studies
    • 42.7. Conclusions
  • Chapter 43. Generating Mouse Models of Mitochondrial Disease
    • 43.1. Introduction to Mitochondrial Disease Genetics and Mechanisms
    • 43.2. Methods for Generating Mouse Models for Mitochondrial Diseases
    • 43.3. Examples of Mouse Models of Nuclear-Encoded Mitochondrial Defects
    • 43.4. Phenotypic Analysis of Mitochondrial Disease in Mouse Models
    • 43.5. Concluding Remarks
• Section VII. Tics
  • Chapter 44. Tics and Tourette Syndrome: Phenomenology
    • 44.1. Introduction
    • 44.2. Phenomenology of Tics
    • 44.3. Clinical Features of Tourette Syndrome
    • 44.4. Neuropsychiatric Comorbidities
    • 44.5. Differential Diagnosis and Pathophysiology of Tics and Tourette Syndrome
  • Chapter 45. Genetics of Tourette Syndrome
    • 45.1. Introduction
    • 45.2. Familial Aggregation Studies
    • 45.3. Heritability and Segregation Studies
    • 45.4. Molecular Studies
    • 45.5. Gene-Expression Studies
    • 45.6. Relevance of Gene–Environment Interactions
    • 45.7. Potential for Pathway Analyses of Genomic Data
    • 45.8. Discussion and Future Directions
  • Chapter 46. Neural Circuit Abnormalities in Tourette Syndrome
    • 46.1. Clinical Characteristics as a Compass to Neuronal Substrates
    • 46.2. Neuronal Correlates of Tic Generation and Tic Output—Findings from Magnetic Resonance Imaging
    • 46.3. Neuronal Correlates of Tic Generation and Tic Output—Findings from Positron Emission Tomography
    • 46.4. Resting State, Fine Motor Skills, and Neuronal Correlates of Voluntary Movements in Tourette Patients—Findings from Behavioral and Imaging Studies
  • Chapter 47. Animal Models of Tourette Syndrome and Obsessive-Compulsive Disorder
    • 47.1. TS Models
    • 47.2. OCD Models
    • 47.3. Conclusions
• Section VIII. Paroxysmal Movement Disorders
  • Chapter 48. Paroxysmal Movement Disorders: Clinical and Genetic Features
    • 48.1. Introduction
    • 48.2. Clinical Features
    • 48.3. Genetics
  • Chapter 49. Mouse Models of PNKD
    • 49.1. PNKD
    • 49.2. Mouse Models of PNKD
    • 49.3. Mouse Models of PNKD—Phenotypes
    • 49.4. Conclusions
  • Chapter 50. Glut1 Deficiency (G1D)
    • 50.1. Introduction
    • 50.2. Disease Mechanisms
    • 50.3. Disease Manifestations
    • 50.4. Treatment
    • 50.5. The G1D Mouse
    • 50.6. Conclusions
  • Chapter 51. Animal Models of Episodic Ataxia Type 1 (EA1)
    • 51.1. Introduction
    • 51.2. mKv1.1V408A/+: A Knockin Murine Model of EA1
    • 51.3. mKv1.1−/−: A Knockout Murine Model of EA1
    • 51.4. rKv1.1S309T/+: A Rat Model of EA1
    • 51.5. mKv1.1ΔC/ΔC: A Megencephaly Mouse Mutant Displaying Ataxia and Seizures
    • 51.6. Concluding Remarks
  • Chapter 52. Mouse Models of Episodic Ataxia Type 2
    • 52.1. Introduction
    • 52.2. Cacna1a Mutations in Mice
    • 52.3. Summary
• Section IX. Tauopathies
  • Chapter 53. Tauopathies: Classification, Clinical Features, and Genetics
    • 53.1. Progressive Supranuclear Palsy
    • 53.2. Corticobasal Degeneration
    • 53.3. Genetics of PSP and CBD
    • 53.4. Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17
    • 53.5. Parkinsonism Dementia Complex of Guam
    • 53.6. Postencephalic Parkinsonism
    • 53.7. Globular Glial Tauopathy
    • 53.8. Summary
  • Chapter 54. Drosophila Models of Tauopathy
    • 54.1. Introduction
    • 54.2. The Double Life of Tau as a Physiologically Indispensable Neuronal Protein and a Neurotoxic Agent
    • 54.3. Methodology: Using Drosophila to Study Tauopathy
    • 54.4. Mechanisms of Tau Toxicity
    • 54.5. Mechanisms Regulating Tau Toxicity
    • 54.6. Neuroprotection against Tauopathy
    • 54.7. Conclusion
  • Chapter 55. Tauopathy Mouse Models
    • 55.1. Introduction
    • 55.2. The Tau Protein
    • 55.3. Mouse Models Relying on Wild-type Human or Mouse Tau
    • 55.4. Transgenic Mice Expressing Mutant Tau Transgenes
    • 55.5. Transgenic Models of FTLD-Tau Splicing Mutations
    • 55.6. Mouse Models of Glial Tau Pathology
    • 55.7. Experimental Induction and Propagation “Seeding” Models
  • Chapter 56. Tau Protein: Biology and Pathobiology
    • 56.1. Introduction—A Brief History of Tau
    • 56.2. Tau Function
    • 56.3. Tau Toxicity
    • 56.4. Tau Pathogenesis in Tauopathies
    • 56.5. Tau Animal Models
    • 56.6. Conclusion
• Section X. Other Parkinsonian Syndromes: NBIA, MSA, PD + Spasticity, PD + Dystonia
  • Chapter 57. Clinical Phenomenology and Genetics of Other Parkinsonian Syndromes Associated with Either Dystonia or Spasticity
    • 57.1. Introduction
    • 57.2. Atypical Parkinsonism—The Classical Parkinson-Plus Syndromes
    • 57.3. Atypical Parkinsonism in Fragile X–Associated Tremor/Ataxia Syndrome
    • 57.4. Dystonic Syndromes with Parkinsonism
    • 57.5. Metal Accumulation Disorders
    • 57.6. Other Dystonia-Parkinsonism Syndromes with Pyramidal Involvement and Often Other Complicating Features
    • 57.7. Miscellaneous Conditions
    • 57.8. Closing Remarks
  • Chapter 58. Animal Models of Multiple-System Atrophy
    • 58.1. Introduction
    • 58.2. Clinical Presentation
    • 58.3. General Considerations
    • 58.4. Animal Models
    • 58.5. Translational Aspects
    • 58.6. Conclusions
  • Chapter 59. Modeling PKAN in Mice and Flies
    • 59.1. Introduction
    • 59.2. Mouse Models
    • 59.3. Drosophila Model for PKAN
    • 59.4. Future Plans
  • Chapter 60. Mouse Models of FA2H Deficiency
    • 60.1. FA2H in the Nervous System
    • 60.2. Fa2h Mutant Mice
    • 60.3. Unanswered Questions
  • Chapter 61. Mouse Models of Neuroaxonal Dystrophy Caused by PLA2G6 Gene Mutations
    • 61.1. Introduction
    • 61.2. Clinical Syndromes Associated with PLA2G6 Mutations
    • 61.3. PLA2G6
    • 61.4. Mouse Models
    • 61.5. Summary and Future Directions
• Section XI. Ataxias
  • Chapter 62. Genetics and Clinical Features of Inherited Ataxias
    • 62.1. Introduction
    • 62.2. Autosomal Recessive Cerebellar Ataxia
    • 62.3. Autosomal Dominant Ataxias
    • 62.4. Spinocerebellar Ataxias
  • Chapter 63. Animal Models of Spinocerebellar Ataxia Type 1
    • 63.1. Introduction
    • 63.2. Uncovering SCA1 Pathogenic Mechanisms via Animal Models
    • 63.3. Concluding Remarks
  • Chapter 64. Mouse Models of SCA3 and Other Polyglutamine Repeat Ataxias
    • 64.1. SCA2 Mouse Models
    • 64.2. SCA3 Mouse Models
    • 64.3. SCA6 Mouse Models
    • 64.4. SCA7 Mouse Models
    • 64.5. SCA17 Mouse Models
    • 64.6. DRPLA Mouse Models
    • 64.7. Therapies for polyQ Diseases
    • 64.8. Conclusions and Lesson Learned
  • Chapter 65. Animal Models of Friedreich Ataxia
    • 65.1. The FRDA Gene, Transcript and Frataxin
    • 65.2. Animal Models
  • Chapter 66. Ataxia-Telangiectasia and the Biology of Ataxia-Telangiectasia Mutated (ATM)
    • 66.1. The Genetics and Biochemistry of AT
    • 66.2. Modeling AT in the Mouse
    • 66.3. The Neurophysiology of AT
    • 66.4. ATM and the Impact of Nongenetic Factors
    • 66.5. Conclusions
  • Chapter 67. Autosomal Recessive Ataxias Due to Defects in DNA Repair
    • 67.1. Introduction
    • 67.2. Endogenous Sources of DNA Damage
    • 67.3. DSB Repair
    • 67.4. SSB Repair
    • 67.5. Diseases Associated with Defects in SSB Repair
    • 67.6. Tyrosyl DNA Phosphodiesterase 1
    • 67.7. Spinocerebellar Ataxia with Axonal Neuropathy 1
    • 67.8. Microcephaly, Infantile-Onset Seizures, and Developmental Delay (MCSZ)
    • 67.9. X-Linked Mental Retardation (XLMR)
    • 67.10. Ataxia Oculomotor Apraxia 1
    • 67.11. Ataxia Oculomotor Apraxia 2
    • 67.12. Neurodegeneration: Consequence of Repair Defects in the Nucleus, Mitochondria, or Both?
    • 67.13. Animal Models and Future Research
  • Chapter 68. Caenorhabditis elegans Models to Study the Molecular Biology of Ataxias
    • 68.1. Introduction
    • 68.2. The Use of C. elegans to Investigate the Molecular Basis of Human Ataxias
    • 68.3. Final Remarks
• Section XII. Hereditary Spastic Paraplegia
  • Chapter 69. Hereditary Spastic Paraplegias: Genetics and Clinical Features
    • 69.1. Introduction
    • 69.2. Differential Diagnosis
    • 69.3. Epidemiology and Genetics
    • 69.4. Neuropathology
    • 69.5. Treatments and Emerging Diagnostics
    • 69.6. Conclusions
  • Chapter 70. Mouse Models of Autosomal Dominant Spastic Paraplegia
    • 70.1. Introduction
    • 70.2. SPG4/Spastin KO Models
    • 70.3. SPG31/REEP1 KO Model
    • 70.4. SPG6/NIPA1 Transgenic Rats
    • 70.5. SPG10/KIF5A Null and Conditional Mutant Mice
    • 70.6. SPG17/BSCL2/Seipin Transgenic Mice
    • 70.7. SPG13/HSPD1/HSP60 mutant mice
    • 70.8. Conclusion and Future Directions
  • Chapter 71. Murine Models of Autosomal Recessive Hereditary Spastic Paraplegia
    • 71.1. Introduction
    • 71.2. SPG5
    • 71.3. SPG7
    • 71.4. SPG20
    • 71.5. SPG21
    • 71.6. SPG26
    • 71.7. SPG30
    • 71.8. SPG39
    • 71.9. SPG44
    • 71.10. SPG47, SPG48, SPG50–52
    • 71.11. ALS2
    • 71.12. Conclusions
  • Chapter 72. Modeling Hereditary Spastic Paraplegia (HSP) in Zebrafish
    • 72.1. Spastin
    • 72.2. Katanin
    • 72.3. Protrudin
    • 72.4. Strumpellin
    • 72.5. Spatacsin, Spastizin, GBA2, and AT-1
    • 72.6. Alsin
    • 72.7. Atlastin and BMP Signaling
    • 72.8. Conclusion
  • Chapter 73. Drosophila Models of Hereditary Spastic Paraplegia
    • 73.1. Introduction
    • 73.2. Genes with Drosophila Mutants that Have Been Studied as Models of HSP
    • 73.3. Genes with Drosophila Mutants Not Studied in the Context of HSP
    • 73.4. Genes without Existing Drosophila Mutants
    • 73.5. Conclusion
  • Chapter 74. Caenorhabditis elegans Models of Hereditary Spastic Paraplegia
    • 74.1. Use of Caenorhabditis elegans to Study HSP
    • 74.2. HSP Caused by SPAST Mutations
    • 74.3. HSP Caused by NIPA1 Mutations
    • 74.4. HSP Caused by Kinesin Gene Mutations
    • 74.5. Conclusions
  • Chapter 75. Use of Arabidopsis to Model Hereditary Spastic Paraplegia and Other Movement Disorders
    • 75.1. Introduction: Similarities between Human and Plant Cells
    • 75.2. Similarities of Arabidopsis and Other Plants with Respect to Movement Disorder Pathways
    • 75.3. Endogenous Plant Compounds May Protect against Movement Disorders
    • 75.4. Summary
• Section XIII. Restless Legs Syndrome
  • Chapter 76. Clinical Phenotype and Genetics of Restless Legs Syndrome
    • 76.1. Introduction
    • 76.2. Epidemiology
    • 76.3. Definition
    • 76.4. The Clinical Phenotype
    • 76.5. Therapy
    • 76.6. Augmentation
    • 76.7. Primary and Secondary RLS
    • 76.8. RLS Mimics
    • 76.9. RLS as a Genetic Disorder
    • 76.10. Family Studies of RLS
    • 76.11. Candidate Gene Association Studies
    • 76.12. GenomeWide Association Studies
    • 76.13. Following-up on GWAS
    • 76.14. Future Directions in RLS Genetics
  • Chapter 77. Combined D3 Receptor/Iron-Deficient Mouse Model
    • 77.1. Combined D3 Receptor/Iron-Deficient Mouse Model
    • 77.2. Iron Deficiency and Dopamine D3 Receptor Dysfunction as Possible Pathogenetic Factors
    • 77.3. Rationale of a Combined Model of D3R and Iron Deficiency
    • 77.4. Effects of Combined Iron and Dopamine D3 Receptor Deficiency on Different Aspects of Murine Behavior
    • 77.5. Conclusion
  • Chapter 78. Use of Drosophila to Study Restless Legs Syndrome
    • 78.1. A Possible Genetic Basis for Restless Legs Syndrome
    • 78.2. Drosophila as a Powerful Platform for Gene Function Analysis In vivo
    • 78.3. Drosophila Is a Suitable Model to Investigate Locomotor and Sleep Phenotypes in RLS
    • 78.4. Findings from a Reverse Genetic Model of RLS/Willis-Ekbom Disease in Flies
    • 78.5. Potential Role for Dopamine and Iron in RLS as Inferred from the Fly Model
    • 78.6. Drosophila as a Discovery Pipeline for Gene Networks in RLS and Sleep Regulation
  • Chapter 79. The A11 Lesion/Iron Deprivation Animal Model of Restless Legs Syndrome
    • 79.1. Background
    • 79.2. Methods: Creating the Model
    • 79.3. Methods—Evaluating the Phenotype
    • 79.4. Methods: Immunohistochemistry to Confirm Lesioning Placement, Neurotransmitter Status, and Iron Status
    • 79.5. Primary Results: Dopamine Cell Histology, Iron Analysis, and Behavioral Effects
    • 79.6. Pharmacological Intervention Experiments
    • 79.7. Determining the Effects of the Model on Spinal Cord Dopamine Receptors: Methods
    • 79.8. Neurotransmitter and Receptor Results
    • 79.9. Long-term Effects of Dopamine Agonist Treatment on Spinal Cord Receptors: Investigating Mechanism of Augmentation
    • 79.10. Results of Long-term Treatment
    • 79.11. Future Directions
  • Chapter 80. Btbd9 Knockout Mice as a Model of Restless Legs Syndrome
    • 80.1. Background on Restless Legs Syndrome
    • 80.2. Biology of BTBD9
    • 80.3. Btbd9 Knockout Mice
    • 80.4. Discussion
• Index