Transcriptional dysregulation of TrkA associates withneurodegeneration in Spinocerebellar Ataxia 17 Pubblico

Abstract

Abstract TATA binding protein (TBP), a universal transcription factor, is required for the initiation of transcription from all three RNA polymerases. It contains a polymorphic polyglutamine tract in its N-terminal region, and expansion of this tract leads to Spinocerebellar Ataxia type 17 (SCA17), one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine expansion in the affected proteins. The expanded polyglutamine proteins are ubiquitously expressed but cause selective neurodegeneration in distinct brain regions in each disease. Unlike many other polyglutamine proteins whose function remains to be fully understood, TBP is a well- characterized transcription factor and is largely distributed in the nucleus. Thus, investigation of how mutant TBP mediates neuropathology will help elucidate the mechanisms by which gene dysregulation mediates neuropathology in polyglutamine diseases. We characterized cellular and mouse models expressing mutant TBP with polyglutamine expansion. The cell model exhibits characteristic features of neuronal dysfunction, including decreased cell viability and defective neurite outgrowth. The high affinity nerve growth factor receptor, TrkA, is down-regulated by mutant TBP. The down- regulation of TrkA also occurs in the cerebellum of SCA17 transgenic mice prior to Purkinje cell degeneration. Furthermore, mutant TBP binds more Sp1, reduces its occupancy of the TrkA promoter, and inhibits the activity of the TrkA promoter. These findings suggest that the transcriptional down-regulation of TrkA by mutant TBP contributes to SCA17 pathogenesis.

Table of Contents

Table of Contents Chapter 1: General Introduction 1 1.1 The Polyglutamine Diseases 2 1.2 Neuropathology of Polyglutamine Disease 4 1.3 Transcriptional Dysregulation in Polyglutamine Disease 6 1.4 Spinocerebellar Ataxia 17 9 1.5 Structure and Function of TATA-Binding Protein 12 Chapter 2: Characterization of a PC12 Cell Model of SCA17 24 2.1 Abstract 25 2.2 Introduction 25 2.3 Materials and Methods 28 2.4 Results 32 2.5 Discussion 36 Chapter 3: Decreased TrkA in Cellular and Mouse Models of SCA17 62 3.1 Abstract 63 3.2 Introduction 63 3.3 Materials and Methods 66 3.4 Results 69 3.5 Discussion 74

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics Biology, Neuroscience
Parola chiave	polyglutamine disease
Committee Chair / Thesis Advisor	Li, Xiao-Jiang, Emory University
Committee Members	Jin, Peng, Emory University Lucchesi, John, Emory University Moberg, Kenneth H, Emory University Caspary, Tamara, Emory University

Ultima modifica

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	Transcriptional dysregulation of TrkA associates withneurodegeneration in Spinocerebellar Ataxia 17 ()	2018-08-28 13:30:30 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions