Drosophila: A Toolbox for the Study of Neurodegenerative Disease: Vol 60

by Mudher; Amritpal

• ISBN13: 9780415411851
• ISBN10: 0415411858
• Edition: 1st
• Format: Nonspecific Binding
• Copyright: 2008-01-28
• Publisher: Taylor & Franci

Summary

Drosophila gives an overview of the ways in which Drosophila is currently being used as a model organism to further our understanding of a spectrum of human neurological diseases. Each chapter is written by respected researchers and gives an excellent account of the subject that is suitable for postgraduate and postdoctoral researchers.

Table of Contents

Contributors	p. ix
Preface	p. xi
Modelling neurodegenerative diseases in Drosophila	p. 1
Background	p. 1
Modelling neurodegenerative diseases in Drosophila	p. 2
How has Drosophila been used to study human diseases?	p. 2
Forward genetics - mutagenesis	p. 2
Reverse genetic approaches	p. 4
Drosophila is an insect	p. 4
References	p. 5
Drosophila genetics for the analysis of neurobiological disease	p. 9
Introduction	p. 9
The life cycle of Drosophila melanogaster	p. 10
The nervous system at key developmental stages	p. 11
Genetic techniques	p. 13
The P-element as a vector	p. 16
Advanced genetic techniques	p. 18
Conclusions	p. 20
References	p. 20
Using Drosophila models to unravel pathogenic mechanisms that underlie neurodegeneration in tauopathies	p. 25
Introduction	p. 25
Does tau play a role in neurodegeneration? Lessons from tauopathies	p. 25
How is tau abnormal in tauopathies?	p. 26
Drosophila models of tauopathies	p. 26
Overexpression of tau is toxic	p. 27
Overexpression of tau disrupts neuronal function	p. 27
Tau disrupts axonal transport	p. 27
Overexpression of tau precipitates a behavioural phenotype	p. 28
Overexpression of tau disrupts synaptic structure and function	p. 29
Phosphorylation state of tau underlies the tau phenotypes	p. 32
Clearance of tau alleviates its toxicity	p. 35
Conclusions	p. 36
References	p. 36
Modelling cell and isoform type specificity of tauopathies in Drosophila	p. 39
Introduction	p. 39
Modelling tauopathies	p. 40
Cell type-specific processing of human tau proteins in Drosophila	p. 41
Phenotypic similarities and differences of tau overaccumulation	p. 42
Differential tissue-specific phosphorylation	p. 46
Modelling tau-dependent learning and memory deficits	p. 47
Excess tau in mushroom body neurons results in learning and memory deficits	p. 48
Isoform-specific effects on learning	p. 49
Conclusions	p. 51
References	p. 53
Using a Drosophila model of Alzheimer's disease	p. 57
Introduction	p. 57
The success of fly models of neurodegenerative diseases	p. 58
Making a model of Alzheimer's disease	p. 58
The secretases and A[beta] generation	p. 59
Genetics supports the primacy of A[beta] toxicity	p. 59
Biochemistry supports the primacy of A[beta] toxicity	p. 61
Problems with mouse models	p. 61
Advantages of Drosophila as a model organism	p. 62
Drosophila models of Alzheimer's disease	p. 62
Generation, optimisation and quantitation of phenotypes	p. 63
Histology	p. 63
Pavlovian olfactory learning assays	p. 63
Longevity	p. 64
Locomotor/climbing	p. 65
Rough eye/pseudo-pupil	p. 66
Genetic screens in a Drosophila model of Alzheimer's disease yield pathogenic pathways	p. 67
Chemical mutagenesis screens	p. 68
Deletion kit screens	p. 68
P-element based screens	p. 69
Identification of candidate genes	p. 70
Drosophila genes with human homologues	p. 70
Clinical relevance	p. 71
Conclusion	p. 71
References	p. 71
Amyloid peptides and ion channel function in Drosophila models of Alzheimer's disease	p. 79
Introduction	p. 79
Vertebrate models of Alzheimer's disease	p. 80
Caenorhabditis elegans models of Alzheimer's disease	p. 81
Drosophila melanogaster models of Alzheimer's disease	p. 83
Fly models used to date in studies of Alzheimer's disease	p. 83
A new Drosophila model for investigating Alzheimer's disease	p. 85
Studies on the Drosophila larval nervous system	p. 85
Electrophysiological studies on neuronal cultures - detection of ligand-gated and voltage-gated ion channels	p. 86
Actions of [beta]-amyloid peptides on A-type K[superscript +] currents of larval neurons	p. 87
Future functional and gene expression studies on the larval nervous system	p. 87
Conclusions	p. 88
References	p. 88
Genetic models of Parkinson's disease: mechanisms and therapies	p. 93
Introduction	p. 93
The [alpha]-synuclein transgenic Drosophila model of Parkinson's disease	p. 94
Generation and characterisation	p. 94
Applications of the Drosophila [alpha]-synuclein model	p. 97
Caveats of the Drosophila [alpha]-synuclein model	p. 99
Loss-of-function models of Parkinson's disease	p. 101
Functional analysis of a Drosophila parkin orthologue	p. 101
Mutational analysis of the Drosophila DJ-1 gene family	p. 104
Functional analysis of a Drosophila PINK1 orthologue	p. 106
Conclusions	p. 108
References	p. 109
Modelling lysosomal storage disease in Drosophila	p. 115
Introduction	p. 115
Classifying the LSD based on stored material and genetic deficits	p. 116
The neuronal phenotype of lysosomal storage	p. 122
Functional consequences of lysosomal storage	p. 123
Current Drosophila models of known LSDs	p. 124
A Drosophila model of Niemann-Pick type C	p. 124
Drosophila models of neuronal ceroid lipofuscinosis	p. 126
Generating novel Drosophila models of LSDs	p. 127
Possible Drosophila models of LSDs	p. 130
Conclusions and outlook	p. 131
References	p. 132
Drosophila melanogaster in the study of epilepsy	p. 141
Introduction	p. 141
Epilepsy models	p. 142
Seizure phenotypes in Drosophila	p. 143
The bang-sensitive group of flies as models for understanding epilepsy	p. 143
The bang-sensitive genes	p. 147
Temperature-sensitive mutants	p. 148
Anaesthesia-induced seizure flies	p. 149
Flies and anti-epileptic drugs	p. 150
Seizure-suppressor genes: candidates for novel anti-epileptics	p. 151
Seizure-enhancer genes	p. 152
Neuronal homeostasis and contribution to seizure	p. 152
Concluding remarks	p. 154
References	p. 155
Hereditary spastic paraplegia genes in Drosophila: dissecting their roles in axonal degeneration and intracellular traffic	p. 161
Introduction	p. 161
Pathogenesis and gene roles	p. 162
Axonal transport	p. 162
Membrane trafficking	p. 168
Mitochondrial proteins	p. 172
Interactions of neurons with substrates or neighbouring cells	p. 173
Conclusion	p. 174
References	p. 175
Triplet repeat diseases: the role of fly models in understanding disease mechanisms and designing possible therapies	p. 183
Triplet repeat disorders	p. 183
Diseases caused by expansions of glutamine repeats	p. 183
Huntington's disease	p. 184
Long polyglutamines and aggregates	p. 185
Diseases caused by expansions/duplications of alanine repeats	p. 185
Oculopharyngeal muscular dystrophy	p. 185
Other diseases caused by expansions of polyalanines	p. 186
Long polyalanines and aggregates	p. 186
Lessons from Drosophila models of triplet repeat diseases	p. 187
Drosophila models of polyglutamine diseases	p. 187
Genetic screens using Drosophila models of polyglutamine diseases	p. 190
Drosophila models of polyalanine diseases	p. 191
Triplet repeat diseases and the Wnt pathway	p. 197
Degradation and aggregate-prone proteins	p. 200
Conclusion	p. 204
References	p. 205
Index	p. 215
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