Identification of genetic modifiers of Fragile X-Associated Tremor/Ataxia Syndrome 公开

Abstract

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) is a debilitating late-onset neurodegenerative disorder that occurs in premutation carriers of the expanded CGG repeat in FMR1. FXTAS results in a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism. Though all premutation carriers are at risk, FXTAS is incompletely penetrant, such that only over a third of male premutation carriers develop the phenotype in their lifetime. This dissertation aims to expand our understanding of the mechanism behind the incomplete penetrance and thereby gain insight into potential biomarkers for diagnosis/prognosis as well as potential therapeutic targets for FXTAS.

In Chapter 1 and 2, we use mouse metabolomics and a Drosophila genetic screen to investigate the genetic modifiers of FXTAS and identify 12 genetic modifiers of FXTAS neurotoxicity, highlighting sphingolipid metabolism as a key altered pathway in FXTAS. In Chapter 3, we combine WGS of 110 human FMR1 premutation carriers and Drosophila genetics to identify 19 genetic modifiers of FXTAS CGG-associated neurodegeneration. Furthermore, in Chapter 4, we demonstrate in Drosophila and Neuro2A cells that PSMB5 is a genetic modifier of FXTAS that ameliorates CGG-associated neurotoxicity upon knockdown and identify PSMB5^rs11543947-A as a potential prognostic biomarker.

Table of Contents

List of Figures. 3

List of Tables. 6

INTRODUCTION. 1

CHAPTER 1 : Untargeted Metabolic profiling of a murine model of Fragile X-Associated Tremor/Ataxia Syndrome. 19

ABSTRACT. 20

KEYWORDS. 20

INTRODUCTION. 21

METHODS. 23

RESULTS. 25

DISCUSSION. 33

ACKNOWLEDGEMENTS. 34

SUPPLEMENTAL MATERIALS. 36

Chapter 2: Sphingolipid pathway modulates the neuronal toxicity associated with Fragile X-Associated Tremor/Ataxia Syndrome. 45

ABSTRACT. 46

KEYWORDS. 47

INTRODUCTION. 47

METHODS. 48

RESULTS. 52

DISCUSSION. 58

ACKNOWLEDGEMENTS. 63

SUPPLEMENTAL MATERIALS. 64

CHAPTER 3: Identification of genetic modifiers of FXTAS by combining whole genome sequencing with fly genetics. 71

ABSTRACT. 72

KEYWORDS. 72

INTRODUCTION. 73

METHODS. 74

RESULTS. 77

DISCUSSION. 81

ACKNOWLEDGEMENTS. 83

SUPPLEMENTAL MATERIALS. 84

CHAPTER 4: Targeting PSMB5 may ameliorate neuronal toxicity in Fragile X-Associated Tremor/Ataxia Syndrome. 91

ABSTRACT. 92

KEYWORDS. 92

INTRODUCTION. 93

METHODS. 94

RESULTS. 99

DISCUSSION. 109

ACKNOWLEDGEMENTS. 113

SUPPLEMENTAL MATERIALS. 114

CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS. 119

CONCLUSIONS. 120

FUTURE DIRECTIONS. 121

REFERENCES. 127

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Genetics
关键词	Genetic modifier Metabolomics CGG Neurodegeneration FXTAS Sphingolipids
Committee Chair / Thesis Advisor	Thomas Wingo, Emory University Peng Jin, Emory University
Committee Members	David Cutler, Emory University Michael Gambello, Emory University Stephen Warren, Emory University Stephanie Sherman, Emory University

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