The Role of Oligodendrocyte Dysfunction in Huntington's Disease Open Access

Abstract

Huntington's disease (HD) is a neurodegenerative disorder that is caused by an expanded polyglutamine tract in the N-terminal region of huntingtin. It is characterized by cognitive and behavioral deficits, as well as movement disorders. While mutant huntingtin is expressed ubiquitously, there is preferential degeneration of the medium spiny neurons of the striatum, followed by widespread degeneration in later stages of the disease. It is well known that mutant huntingtin can affect neuronal function by interfering with a number of processes such as gene expression and trafficking. However, the effects of mutant huntingtin on the function of glial cells, in particular oligodendrocytes, remain to be fully investigated. There is increasing evidence of white matter abnormalities in both HD patients and HD mouse models, suggesting that mutant huntingtin might affect oligodendrocyte function. We hypothesize that mutant huntingtin causes oligodendrocyte dysfunction, which contributes to the pathogenesis of the disease. To this end, we generated transgenic mice (PLP-htt) that express an N-terminal fragment of mutant huntingtin exclusively in oligodendrocytes. These mice develop a tremor by 2 months of age and have locomotor and behavioral deficits, including body weight loss, reduced lifespan, and increased seizure susceptibility compared to control mice. Reduced myelin sheath thickness in the striatum, as well as reduced mRNA and protein expression of essential myelin genes, suggest that oligodendrocyte-specfic expression of mutant huntingtin causes an age-dependent dysregulation of myelin gene expression. Additionally, we found that mutant huntingtin binds to a transcription factor, MYRF, which is essential for myelin gene expression and maintenance of myelin. As mutant huntingtin accumulates in the cell, it binds to MYRF so that MYRF is unable to activate the transcription of myelin genes, such as myelin basic protein. We did not observe abnormalities in oligodendrocyte differentiation or proliferation, and myelination and myelin gene expression were normal in young mice. Thus, our findings suggest that mutant huntingtin impairs oligodendrocyte function in adult mice, which results in demyelination and likely contributes to the neuronal degeneration that is observed in Huntington's disease.

Table of Contents

CHAPTER 1: INTRODUCTION

1.1 Polyglutamine Disease Family. 2

1.2 Huntington's Disease. 4

1.3 Neuronal Dysfunction and Death in Huntington's Disease. 6

1.4 Glial Dysfunction in Huntington's Disease. 9

1.5 Mouse Models. 13

1.6 Dissertation Goals. 15

CHAPTER 2: MATERIALS AND METHODS

2.1 Animals. 21

2.2 Reagents. 21

2.3 Mouse Behavior Analysis. 24

2.4 Immunofluorescence, Immunohistochemistry, and Electron Microscopy. 25

2.5 Analysis of Oligodendrocyte Morphology. 26

2.6 BrdU Incorporation Assay. 27

2.7 Cell Culture. 27

2.8 Western Blotting and Co-Immunoprecipitation. 27

2.9 Fluorescence-Activated Cell Sorting of Oligodendrocytes. 28

2.10 Microarray and qRT-PCR. 29

2.11 Luciferase Reporter Assay. 30

2.12 Chromatin-Immunoprecipitation. 31

2.13 GST-Pulldown Assay. 31

2.14 Statistical Analysis. 32

CHAPTER 3: SELECTIVE EXPRESSION OF MUTANT HUNTINGTIN IN OLIGODENDROCYTES CAUSES BEHAVIORAL ABNORMALITIES AND DEMYELINA TION

3.1 Abstract. 34

3.2 Introduction. 34

3.3 Results. 36

3.4 Discussion. 44

CHAPTER 4: MUTANT HUNTINGTIN DOWNREGULATES MYELIN REGULATORY FACTOR-MEDIATED MYELIN GENE EXPRESSION IN MATURE OLIGODENDROCYTES

4.1 Abstract. 83

4.2 Introduction. 83

4.3 Results. 85

4.4 Discussion. 87

CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS

5.1 Summary. 103

5.2 Remaining Questions and Future Directions. 106

5.3 Conclusions. 110

LITERATURE CITED. 113

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics Biology, Neuroscience
Keyword	oligodendrocyte Huntington's disease myelin
Committee Chair / Thesis Advisor	Li, Xiao-Jiang, Emory University
Committee Members	Cubells, Joseph F, Emory University Moberg, Kenneth H, Emory University Feng, Yue, Emory University Bassell, Gary, Emory University

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