Developing a Nonhuman Primate Model of Huntington's Disease Open Access

Yang, Shang-Hsun (2008)

Permanent URL: https://etd.library.emory.edu/concern/etds/5d86p0445?locale=en
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Abstract

Abstract

Developing a Nonhuman Primate Model of Huntington's Disease By Shang-Hsun Yang Huntington's disease (HD) is an inherited autosomal-dominant disease, manifesting itself as a loss of striatal medium spiny neurons leading to a neurodegenerative disorder in humans. Transgenic mice carrying mutant huntingtin ( HTT) provide an in vivo mechanism for HD; however, there are limitations in recapitulating the process of HD in mouse models. In my dissertation work, we developed a non-human primate model of HD that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. The transgenic monkeys also showed key clinical features observed in human HD patients, including dystonia and chorea. In addition, the microRNA (miRNA) expression profile of HD monkeys was investigated in a high-throughput manner, showing that four potential miRNA candidates, Hsa-mir-196a, Hsa-mir-451, Hsa-mir-486 and Hsa-mir-429, and one target gene, CUG triplet repeat RNA binding protein 2 (CUGBP2), may be correlated to HD. The development of behavioral and pathological phenotypes in the HD monkeys without medical intervention suggests our studies could emulate the natural course of human HD. The goal of this study is to better understand the underlying biology of HD and to develop potential therapies for HD.

Table of Contents

TABLE OF CONTENTS

CHAPTER I: GENERAL INTRODUCTION 1 General Information on Huntington's Disease 2 Cellular and Neuropathology of HD 5 Aberrant Gene Regulation in HD 9 Mouse Models of HD and Limitations 16 The Importance and Limitations of A Non-Human Primate Model of HD 20 The Goals for This Dissertation 24

CHAPTER II: ESTABLISHING A NON-HUMAN PRIMATE MODEL OF HUNTINGTON'S DISEASE 26 Introduction 28 Materials and Methods 30 Results 47 Discussion 60

CHAPTER III: DISCOVERY OF NOVEL MICRORNAS IN A NON-HUMAN PRIMATE MODEL OF HUNTINGTON'S DISEASE 116 Introduction 117 Materials and Methods 119 Results 125 Discussion 132

CHAPTER IV: GENERAL CONCLUSION 161

REFERENCES 166

PUBLISHED PAPERS 197

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