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The role of glia in Huntington's disease pathology

Bradford, Jennifer Webster (2010)
Dissertation (141 pages)
Committee Chair / Thesis Adviser: Li, Xiao-Jiang
Committee Members: Escayg, Andrew ; Vertino, Paula M ; Cubells, Joseph ; Benian, Guy
Research Fields: Biology, Neuroscience; Biology, Genetics
Keywords: glia; Huntington's disease; polyglutamine; astrocyte; glutamate transporter
Program: Laney Graduate School, Biological and Biomedical Sciences (Genetics and Molecular Biology)
Permanent url: http://pid.emory.edu/ark:/25593/7tftj

Abstract


The role of glia in Huntington's disease pathology
By Jennifer Webster Bradford


Huntington's disease (HD) is the most common of nine inherited polyglutamine
diseases, and is caused by an expansion of the polyglutamine tract (>36 repeats) in the N-
terminus of the huntingtin (htt) protein. Although mutant htt is ubiquitously expressed
throughout the body, little is known about how it impacts non-neuronal tissues. Previous
work in our lab has demonstrated that glial cells are negatively affected by the presence
of mutant htt, and their dysfunction could contribute to disease progression. Glial cells
are essential components of the central nervous system, and play crucial roles in neuronal
function and cell-cell communication, but little is known about how mutant htt in glia
contribute to HD pathology. To this end, we generated two different HD mouse models
that express N-terminal human mutant htt that is controlled by the glial fibrillary acidic
protein promoter (GFAP), which drives gene expression in astrocytes. This dissertation
describes the results from behavioral and molecular characterization of these novel
mouse models. These studies found that expression of mutant htt in astrocytes was
sufficient to produce a progressive, late onset HD phenotype that included body weight
loss, decreased rotarod ability and early death, when compared with wild type littermates
or control transgenic mice. Molecular analysis aimed at uncovering the possible
mechanisms underlying these phenotypes revealed that the HD mice expressing mutant
htt in astrocytes had glutamate transporter defects. It was found that the glutamate
transporter defects were due to improper binding of mutant htt to the Sp1 transcription
factor, which resulted in decreased gene expression. These results challenge the classic
cell autonomous view of neurodegeneration by implying an important role for glia in HD
pathology. These findings also suggest that treatment of astrocytes might be a viable
target in developing new HD therapies.

Table of Contents

Table of Contents

Chapter 1: General Introduction 1

1.
The polyglutamine disease family 2

1.1 Spinocerebellar ataxias 2
1.2 Spinobulbar muscular atrophy and dentatorubropallidoluysian atrophy 3
1.3 Huntington's disease 4
1.4 Huntington's disease mouse models 8

2. Glial dysfunction in polyglutamine diseases 10
2.1 Types of glia in the central nervous system 11
2.2 Astrocyte glutamate transporters 12
2.3 Reactive gliosis 13
2.4 Glia and Huntington's disease 14

Chapter 2: Characterization of a novel HD mouse model that expresses mutant huntingtin in astrocytes 22
2.1 Abstract 23
2.2 Introduction 24
2.3 Materials and Methods 25
2.4 Results 28
2.5 Discussion 34

Chapter 3: Mutant huntingtin expression in mouse brain astrocytes
results in glutamate transporter dysfunction 60
3.1 Abstract 61
3.2 Introduction 62
3.3 Materials and Methods 63
3.4 Results 67
3.5 Discussion 71

Chapter 4: Characterization of a BAC transgenic HD mouse model
that expresses mutant htt in astrocytes 90
4.1 Abstract 91
4.2 Introduction 92

4.3 Materials and Methods 93

4.4 Results 95

4.5 Discussion 96

Chapter 5: General conclusions and future directions 110

5.1 General Conclusions 111

5.2 Future Directions 116

References 121

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