Translational Models of Parkinson’s Disease and related Movement Disorders

1st Edition - November 26, 2024
Editor: Wael Mohamed
Language: English
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eBook ISBN:
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Translational Models of Parkinson’s Disease and Related Movement Disorders focuses on cutting-edge techniques for creating and validating current Parkinson’s Disease translati… Read more

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Translational Models of Parkinson’s Disease and Related Movement Disorders focuses on cutting-edge techniques for creating and validating current Parkinson’s Disease translational experimental models. Various characteristics of these models are examined, including the prion-like properties of -synuclein, mitochondrial functions connected to the PINK1-Parkin pathway/CHCHD2, the endolysosome pathway connected to LRRK2, VPS35, and ATP13A2 using cultured cells (including patient iPS cells). This book also highlights the future possibilities of introducing new models for Parkinson’s Disease and related movements disorders, underscoring current advancements, pre-clinical and clinical developments, and future scope related to numerous models.

Title of Book
Cover image
Title page
Table of Contents
Copyright
Dedication
Contributors
Preface
Acknowledgments
Section I. Understanding PD and related movement disorders
Chapter 1. Neuroinflammation, glymphatic system, and Parkinson's disease
1 Parkinson's disease: exploring the interplay of neuroinflammation and the glymphatic system
2 Neuroinflammation
2.1 Definition and types of neuroinflammation
2.2 The cellular and molecular mechanisms
2.3 Crucial routes involved in neuroinflammation comprise
2.4 Astrocyte participation
2.5 The relationship between neuroinflammation and neurodegeneration
3 The glymphatic system
3.1 Waste clearance pathways
4 Microglia role in PD neuroinflammation
5 Monocyte role in neuroinflammation
6 Astrocyte role in PD neuroinflammation
7 Peripheral immune cell-mediated inflammation role in PD
8 Biomarkers of neuroinflammation in Parkinson's disease
9 Interleukins
10 NF-α/sTNFRs
11 Beta-amyloid 1–42, tau, p-tau
11.1 Alpha-synuclein
11.2 Genetic biomarkers in PD
11.3 Imaging biomarkers
11.3.1 Computational approaches to biomarker identification
12 The importance of early diagnosis
13 Clinical biomarker
14 Hyposmia
15 REM behavior sleep disorder
15.1 Neuroimaging analysis
16 Diffusion tensor imaging
17 Positron emission tomography
18 single-photon emission computed tomography
19 Therapeutic approaches of neuroinflammation and glymphatic system disturbance in Parkinson disease
19.1 Challenges with neurotrophic factors
19.2 Antiinflammatory therapies in PD
19.3 Current clinical trials for antiinflammatory disease modification in PD
20 Conclusion
Chapter 2. Pharmacotherapy of PD and related movements disorders and their limitations
1 Introduction to Parkinson's disease and related movement disorders
1.1 Definition and overview of Parkinson's disease and related disorders
1.2 Epidemiology and prevalence
1.3 Pathophysiology
1.4 Symptoms of PD and related disorders: Distinguishing motor and nonmotor
1.5 Progression of the disease and its impact on treatment decisions
2 Pharmacotherapy for Parkinson's disease
2.1 Overview of pharmacological agents used in PD
2.2 Levodopa: Mechanism of action, benefits, and side effects
2.3 Dopamine agonists and MAO-B inhibitors in Parkinson's disease: Efficacy, usage, and safety
2.4 MAO-B inhibitors: Role in PD management, efficacy, and safety concerns
2.5 Anticholinergics, other medications, and personalized medicine in Parkinson's disease treatment
2.6 Other medications: Amantadine and NMDA receptor antagonists
2.7 Personalized medicine approach in PD treatment
3 Treatment of related movement disorders: Differentiating pharmacotherapy
3.1 Essential tremor
3.2 Dystonia
3.3 Huntington's disease
4 Limitations and challenges in pharmacotherapy
4.1 Drug resistance and diminishing efficacy
4.2 Side effects management, nonmotor symptoms challenges and managing advanced PD and related disorders
5 Adjunct therapies and multidisciplinary approach in Parkinson's disease and related movement disorders
5.1 Role of physical, occupational, and speech therapy
5.2 Psychosocial support
5.3 Diet and lifestyle modifications
6 Emerging treatments and future directions in Parkinson's disease
6.1 New pharmacological agents and strategies
6.2 Gene therapy and stem cell therapy
6.3 Technology in treatment management
7 Conclusion
Chapter 3. Diagnosis and biomarkers of Parkinson's disease and related movement disorders
1 Introduction
2 Diagnosis of Parkinson's disease
2.1 Clinical diagnosis (Table 3.1)
2.2 Differential diagnosis
2.3 Imaging and laboratory tests
3 Biomarkers in Parkinson's disease
3.1 Biochemical biomarkers
3.1.1 Biofluid biomarkers
3.1.2 MicroRNAs as diagnostic tools for PD
3.2 Neuroimaging biomarkers
3.2.1 Dopaminergic imaging
3.3 Genetic biomarkers
3.3.1 Genetic testing and counseling
3.3.2 Risk alleles
3.3.3 Genetic risk scoring
3.3.4 Mendelian mutations
3.4 Multimodal biomarkers
3.5 Non-invasive biomarkers
3.5.1 Voice and speech analysis
3.5.2 Gait analysis
3.5.3 Eye movements
3.5.4 Olfactory testing
4 Biomarkers in other movement disorders
4.1 Huntington's disease
4.2 Dystonia
4.3 Essential tremors
5 Challenges and future directions
5.1 Limitations and challenges of current biomarkers
5.2 Potential new biomarkers
5.3 Future implications of biomarkers
6 Conclusion
Chapter 4. OMICS and bioinformatics in Parkinson disease and related movements disorders
1 Introduction and Background
1.1 Introduction
1.2 PD gene mutations that are passed from generation to generation
1.2.1 The PARK1 locus is SNCA (α-synuclein)
1.2.2 LRRK2 (leucine-rich repeat kinase 2), also known as the PARK8 locus
1.2.3 Mutations in the enzyme known as glucocerebrosidase (GBA1)
1.2.4 DJ-1 mutation
1.2.5 SMPD1 mutations
2 High-throughput sequencing techniques are being used to discover the causative genes related to PD disease
2.1 The use of GWAS in PD
2.2 The use of WES in PD
2.3 Using WGS in PD
3 Parkinson's disease and omics
3.1 Lipidomics
3.2 Genomics
3.3 Metabolomics
3.3.1 Key analytical platforms utilized in metabolomics research
3.3.2 Metabolomics of sebum in Parkinson's disease
3.4 Proteomics
3.5 Challenges encountered in utilizing omics technologies in the study of the genetics of Parkinson's disease and other related movement disorders
4 Other movement-related disorders
4.1 Urge phenomenon
Chapter 5. Modeling Parkinson's disease with the alpha-synuclein protein
1 Historical overview
2 Structure and function of alpha-synuclein
2.1 Structure of alpha-synuclein
3 Function of alpha-synuclein
4 Neuroprotective, synaptic functions, and neurotransmitter release
5 Metabolic regulation and calcium signaling
6 Chaperone activity and interaction with heat shock proteins (HSPs)
6.1 Synucleinopathies: Key role in neurodegenerative disorders
7 Other functions
8 Genetic aspects of alpha-synuclein
8.1 SNCA gene
9 Polymorphism within the SNCA locus
9.1 Other genes at SNCA locus
10 Therapeutic interventions of alpha-synuclein's protein
11 Therapeutic strategies for Parkinson's using alpha-synuclein
12 Targeting αSyn accumulation: Pros and cons
13 αSyn targeted therapies
14 Alpha-synuclein model
15 Alpha-synuclein aggregation formation
16 Conclusion
Chapter 6. α-Synuclein seeding assay and analysis
1 Introduction
2 Parkinson's disease
3 Alpha-synuclein structure and its physiological function
4 Development of α-syn seeding assays
5 α-Syn seed amplification assays in CSF
5.1 AbbVie α-syn-SAA method
5.2 PMCA by Amprion lab
5.3 RT-QuIC by Caughey laboratory
5.3.1 Diagnostic performance of three methods for PD
6 α-Synuclein seeds as serum biomarkers
7 Conventional assays for α-syn detection
8 Conclusion
Section II. Mammalian models of Parkinson's disease
Chapter 7. SHH, nurr1, pitx3, and en1 models for Parkinson's disease
1 Introduction
2 SHH
2.1 Pathway of Sonic Hedgehog signaling in Parkinson's disease
2.2 Primary cilia pathway related to SHH
3 Nurr1
3.1 Role of Nurr1 in Parkinson's disease
3.2 The involvement of NURR1 in the inflammatory response mediated by α-Synuclein
3.3 The influence of NURR1 on neuroinflammation resulting from mitochondrial dysfunction and oxidative stress
3.4 Nurr1 in the treatment of Parkinson's disease
4 Pitx3
5 En1
5.1 Engrailed
5.2 Significance statement
6 Conclusion
Chapter 8. Stem cell for PD: Technical considerations
1 Historical milestones in stem cell research
2 Overview of Parkinson's disease and stem cell therapy
3 Technical considerations in stem cell therapy
4 Human and induced pluripotent stem cells
5 Mesenchymal stem cells
6 Meta-analysis in Parkinson's disease
7 Challenges and risks
7.1 Addressing immune response and minimizing risk of rejection
8 Legal and ethical frameworks guiding stem cell research
9 Current research and clinical trials
10 Future directions and innovations
Chapter 9. Deep brain stimulation using animal models of Parkinson's disease
1 Introduction
2 Deep brain stimulation
2.1 Deep brain stimulation history
3 Parkinson disease and subtypes of Parkinson disease
4 Animal models of Parkinson disease
4.1 Brain-first subtype animal models
4.1.1 Neurotoxins
4.1.2 Viral vector-mediated asyn overexpression
4.1.3 Injection of fibrillar forms of asyn into the brain—“Seeding”
4.1.4 Transgenic models: The role of elevated asyn levels
4.2 Body-first animal models
4.2.1 Viral vector-mediated body-first models
5 Mechanism of deep brain stimulation and Parkinson disease
6 Conclusion
Chapter 10. The MitoPark mouse model of Parkinson's disease
1 Introduction
1.1 Parkinson's disease (PD)
1.2 Animal models used for PD
1.2.1 The progressive neurodegeneration and Parkinsonism phenotype in Mito Park mice summary
2 Parkinson's disease models (Table 10.1)
2.1 Nonmammalian species
2.1.1 Fruit fly (Drosophila)
2.1.2 Nematode C. elegans
2.1.3 Zebrafish
2.2 Rodents
2.3 Nonhuman primates (NHP)
2.4 Induced pluripotent stem cell (iPSC)-derived PD model
3 Mechanisms of Parkinson's disease (PD) models
3.1 Neurotoxin models
3.1.1 6-Hydroxydopamine (6-OHDA)
3.1.2 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
3.1.3 Paraquat (PQ)
3.1.4 Rotenone
3.2 Genetic models
3.2.1 Leucine-rich repeat kinase 2 (LRRK2)
3.2.2 Parkin
3.2.3 Protein deglycase (DJ-1)
3.2.4 Pten-induced kinase 1 (PINK1)
4 PD correlation to the mitochondria
5 The role of mitochondrial DNA mutations and complex I deficiency
6 Mitochondrial dysfunction and oxidative stress
7 The role of mitochondrial DNA
8 Establishing the MitoPark mouse
9 Characterization of the MitoPark mouse
10 MitoPark mouse impaired respiratory chain function
10.1 The inhibition of complex I results in an increase in ROS superoxide generation
10.2 MitoPark mice startle
10.3 Electrophysiological parameters in the Mitropark mouse
11 PD in Mitopark mouse model and its correlation to neuroinflammation
12 Treatment response
13 Conclusion
Chapter 11. The beta-sitosterol beta-D-glucoside (BSSG) rat model of Parkinson's disease
1 Introduction
2 Parkinson's disease
2.1 Pathogenesis of Parkinson’s disease
2.1.1 α-Synuclein misfolding and aggregation
2.1.2 Mitochondrial dysfunction
2.1.3 Dysfunctional protein clearance systems
2.1.4 Neuroinflammation
2.2 Symptomatic treatment for Parkinson's disease
3 The BSSG model
3.1 Background
3.2 Motor characteristics
3.3 Prodromal traits
3.4 Cognitive impairments
3.5 α-Synuclein pathology
3.6 Effectivity of action
3.7 The advantages of the BSSG model
4 Neuroprotective therapies using the BSSG model
5 Limitations of using the BSSG model for PD
6 Conclusion
Section III. Invertebrate models of Parkinson's disease
Chapter 12. SCA1 zebrafish model
1 Introduction
2 Spinocerebellar ataxia type 1 (SCA1)
3 Molecular mechanisms of neurodegeneration
4 The role of protein aggregates
5 Neurobehavioral phenotyping
6 Paresis and paralysis
7 Balance and coordination
7.1 Evidence for links to protein to neurodegenerative disorder
7.2 Alpha-synuclein
7.3 Parkin and PINK1
7.4 DJ-1
7.5 LRRK2
8 Hypokinetic movement disorders
9 Parkinsonism in spinocerebellar ataxia
10 PD-related proteins affect intrinsic mitochondrial functions
10.1 Mitochondrial dysfunction in autosomal dominant Parkinson's disease
10.1.1 SNCA
10.1.2 LRRK2
10.2 Mitochondrial dysfunction in autosomal recessive Parkinson's disease
10.2.1 Parkin
10.2.2 PINK1
11 Modeling of SCA1 in zebrafish
12 Plasmid vectors for microinjection
12.1 pA-4xmir181aT-GAPmScarlet-E1b-8×ca8-E1b-4xmir181aT-pA (stock no. #5158)
12.2 pA-4xmir181aT-GAPmScarlet-E1b-8×ca8-E1b-HA:Atx1[30Q]-4xmir181aT-pA (stock no. #3417)
12.3 pA-4xmir181aT-GAPmScarlet-E1b-8×ca8-E1b-HA:Atx1[82Q]-4xmir181aT-pA (stock no. #5187)
13 Microinjection of nucleic acids
13.1 Results
13.1.1 Genetic modeling of SCA1 in zebrafish
13.1.2 Age-related progressive disturbances of Purkinje cell layer integrity in zebrafish genetic model of SCA1
13.1.3 Behavioral performance of zebrafish SCA1 model
14 Conclusion
Chapter 13. Various zebrafish models of Parkinson's disease: What gives us hope
1 Introduction
2 Available animal models to study and conduct research on PD
3 What are zebrafish?
4 Understanding the behavioral neuroscience of zebrafish animals
5 Using zebrafish as an animal model: Advantages and disadvantages
6 Challenges of the zebrafish model
7 Zebrafish as a model for Parkinson's disease
8 Neurotoxin-induced zebrafish model of PD
8.1 Transgenic zebrafish models of PD
8.2 PINK1 gene mutation
8.3 DJ-1 gene mutation
8.4 α-synuclein (SNCA) gene
8.5 Parkinson's disease protein 2 (PARK2) gene
8.6 Parkinson's disease protein 7 (PARK7) gene
8.7 LRRK2 gene
9 Defined toxins associated with PD
9.1 Rotenone
9.2 Paraquat
9.3 Ziram
9.4 Benomyl
9.5 Diesel exhaust particle extracts
10 Use of gene editing technology in zebrafish (Ünal & Emekli-Alturfan, 2019)
11 Zebrafish models for the functional genomics of neurogenetic disorders
12 Conclusion
Chapter 14. Drosophila PD model
1 Introduction
2 Parkinson's disease
3 Symptoms
4 Current symptoms relief medications
5 Mechanism
6 Causes and risk factors
7 The history of Drosophilaas a model organism
8 Chromosomes of Drosophila
9 Advantages of using D. melanogaster as a model organism
10 Drosophila as a PD model
10.1 Alpha-synuclein models
10.2 Parkin mutation
10.2 DJ-1
11 Advanced therapeutic approaches of PD using the Drosophila model
11.1 Therapeutic approaches based on natural products
11.2 Therapeutic approaches based on herbal products
12 Chemotherapeutic approaches
13 Gene therapy
14 Conclusion
Chapter 15. Caenorhabditis elegans models of tauopathy
1 C. elegans
1.1 Natural history of the life C. elegans
2 C. elegans nervous system and developmental plasticity
2.1 Genetics
3 Tau protein and tauopathies
3.1 Physiology
3.2 Localization
3.3 Tau protein conformational changes in neurodegenerative diseases
3.4 The role of MAPT gene mutations in tauopathies
3.5 Tau aggregates and toxicity in C. elegans neurons
3.6 C. elegans as a model for protein misfolding diseases: Investigating the role of PTL-1 in neuronal function and regulation
4 The utilization of C. elegans as a valuable experimental tool
4.1 Transgenic C. elegans as a model organism for investigating neurodegenerative diseases
4.2 Expression system choices for C. elegans models of tauopathies
4.2.1 C. elegans pan-neuronal gene expression regulatory models
4.2.2 Models of mechanosensory gene expression regulation: Insights and possibilities
5 PRE- and postsynaptic abnormalities
6 Therapeutic interventions tested in C. elegans
7 Exploring the potential of C. elegans as a tauopathy model: Future directions, advantages, and limitations
7.1 Advances and challenges in CRISPR-Cas genome editing technology in C. elegans
7.2 Advantages and limitations
8 Conclusion
Chapter 16. LRRK2 in Caenorhabditis elegans model
1 Introduction
2 The LRRK2 gene
3 Structure and physiological functions of LRRK2 protein
3.1 Enzymatic domains
3.2 Protein-protein interaction domains
4 Animal models of LRRK2 mutations
4.1 Cellular cultures
4.2 Rodent models
4.3 Drosophila models
4.4 Caenorhabditis elegans models
5 Caenorhabditis elegans neurobiology
5.1 Taxonomy, anatomy and habitat
5.2 Life cycle
5.3 Reproduction
5.4 Why it is used as a disease model
5.5 Usage as a disease model
6 Caenorhabditis elegans as a model to study LRRK2 in Parkinson disease
6.1 Caenorhabditis elegans LRRK1 knock-off models
6.2 Caenorhabditis elegans LRRK2 transgenic overexpression models
Section IV. Ethics and regulations related to translational PD models
Chapter 17. Confounding factors for validation of PD models
1 Introduction
2 The problem of confounding factors in animal models
3 Embedded confoundings in PD modeling
3.1 Biological and model related confounding factors
3.2 Phenotypic differences
3.3 Disease onset and progression
3.4 Genetic differences
3.5 Genetic variability
3.5.1 Background of the genetic variability in PD
3.5.2 Genetic variability for validation of PD models
3.6 Comorbidities of human PD
4 Validation of animal models
4.1 Internal validity and external validity
4.2 Experimental confounding factors
4.3 Application of validation on PD models
5 Conclusion
Chapter 18. Neurobehavioral characterization of PD models
1 Introduction
2 Characterization of motor symptoms
2.1 Tremors
2.2 Forelimb akinesia
2.3 Bradykinesia
2.4 Rigidity
3 Characterization of nonmotor symptoms
3.1 Depression
3.2 Anxiety
3.3 Cognitive impairment
3.4 Sleep disorders
3.5 Autonomic dysfunction
3.5.1 Bladder dysfunction
3.5.2 Cardiovascular dysfunction
3.5.3 Gastrointestinal tract dysfunction
3.6 Pain
3.6.1 Electrical sensitivity
3.6.2 Mechanical sensitivity
3.6.3 Thermal sensitivity
3.7 Olfactory dysfunction
3.8 Blink reflex abnormality
4 Conclusions and perspectives
Chapter 19. Ethical regulations for induction and validation of PD models
1 Introduction
2 Optimal Parkinson's model
3 Validation of animal models
4 Regulation of animal models
4.1 Replacement
4.2 Reduction
4.3 Refinement
5 Pros and cons of different PD models
5.1 Biochemical and cellular models
5.1.1 α-Synuclein seeding assay and analysis
5.1.2 LRRK2 in tissues and cultured cells
5.1.3 Midbrain dopaminergic neurons and PINK1-Parkin using human iPS cells
5.1.4 Models SHH, Nurr1, Pitx3, and EN1
6 Mammalian models
6.1 6-OHDA, MPTP, and rotenone rodent model of PD
6.2 α-Synuclein mouse models
6.3 MitoPark mouse model
6.4 The BSSG rat model of Parkinson's disease
6.5 Marmoset (Callithrix jacchus) model of α-synuclein
6.6 Invertebrate models
6.6.1 Zebra Fish Model
6.6.2 Drosophila PD model
6.6.3 Caenorhabditis elegans models of PD
7 Conclusion
Chapter 20. The OMICS and PD models: Hopes or hypes
1 Introduction
1.1 Omics trend and progression
1.1.1 Integrating multiomics data in complex disease primary tissues
1.1.2 Rodents
1.1.3 Nonhuman primates
1.1.4 Nonmammalian species
1.1.5 Induced pluripotent stem cell–Derived PD model
1.1.6 Emerging models
1.1.7 6-Hydroxydopamine
1.1.8 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
1.1.9 Paraquat
1.1.10 Rotenone
1.2 Genetic models of PD
1.2.1 α-Synuclein
1.2.2 Parkin
1.2.3 Leucine-rich repeat kinase 2
1.2.4 Protein deglycase
1.2.5 Pten-induced kinase 1
1.2.6 In vitro modeling
1.2.7 Different omics and Parkinson disease
2 Transcriptomics in PD models
2.1 Proteomics
2.2 Proteomics in PD models
2.2.1 Metabolomics
3 Metabolomics for PD models
4 Microbiomics in PD models
4.1 Multiomics approaches for identifying Parkinson disease mechanisms and biomarkers
4.2 Potential for omics-based personalized medicine for PD
5 Conclusion
Chapter 21. Parkinson's disease from an Ayurveda perspective: Opportunities and challenges for further research
1 Introduction
1.1 Introduction to Parkinson's disease
1.2 Dopamine and its altered role in PD
1.3 Causes of PD
1.4 Current treatment of PD
1.5 Need for new treatment modalities
2 Ayurveda and PD
2.1 Ayurveda
2.2 Correlates to PD
2.3 Kampavata
2.4 Case studies in Ayurveda
3 Ayurveda for PD
3.1 Single herbal drugs
3.1.1 Mucuna pruriens
3.1.2 Bramhi (Bacopa monnieri)
3.1.3 Ashwagandha (Withania somnifera)
3.1.4 Bala (Sida cordifolia)
3.1.5 Parisak Yavani (Hyoscamus Niger)
3.2 Ayurvedic panchakarma for prevention of PD
3.3 Massage and hot fomentation for PD
3.4 Panchakarma for PD
3.5 Strengths and limitations of Ayurveda modalities
3.5.1 Strengths of Ayurveda modalities
4 Challenges for Ayurvedic interventions in PD
4.1 Lack of evidence
4.2 Multiple interventions
4.3 Lack of standardization
4.3.1 Gut dysbiosis in PD and Basti Karma in Ayurveda
4.3.2 Nasal administration of the drug in PD
5 Current models used in PD
6 Conclusion
Index

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Translational Models of Parkinson’s Disease and related Movement Disorders

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