Pathogenic Mechanisms in Fragile X Tremor Ataxia Syndrome

a MiCDA Research Project Description

Investigators: Peter Todd, Henry Paulson

Funding: National Institute of Neurological Disorders and Stroke, 2010-2015 (1 K08 NS 069809 01)

Project Abstract

Title: Pathogenic Mechanisms in Fragile X Tremor Ataxia Syndrome
Principal Investigator: Peter Todd, MD, PhD

Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited cause of gait disorder and tremor affecting upwards of 1:800 males. FXTAS is caused by an expanded ?CGG? nucleotide repeat in the 5? untranslated region of the Fragile X Mental Retardation gene, FMR1. In patients and animal models, this expanded CGG repeat is associated with elevated FMR1 mRNA expression, neurodegeneration, and ubiquitin-positive intranuclear neuronal inclusions that contain the expanded CGG repeat mRNA and several proteins. Work to date has focused on the potential role of the CGG repeat in eliciting neurodegeneration via an RNA gain-of-function mechanism. However, critical aspects of disease pathology are not easily explained by a pure mRNA-mediated sequestration process. Our central hypothesis is that the CGG repeat expansion contributes to neuronal degeneration in FXTAS via multiple, overlapping molecular mechanisms. These mechanisms include transcriptional dysregulation of the FMR1 gene in cis and RNA mediated gain of function toxicity leading to anomalous RNA splicing events and alterations in protein quality control pathways. Our proposal to test this hypothesis is divided into three aims. Aim 1 will examine the mechanisms by which FMR1 mRNA transcription is increased, focusing on the histone acetylation status at the FMR1 locus. Aim 2 will examine the role of the ubiquitin proteasome system in FXTAS pathogenesis. Both aims one and two will utilize a fruit fly model of FXTAS as well as patient derived lymphoblasts. Aim 3 will employ inducible pluripotent stem cells from FXTAS patient fibroblasts that are differentiated into neurons. We will then evaluate the alternative transcriptome profile of these human FXTAS neurons to address the hypothesis that sequestration of RNA binding proteins is a critical event in FXTAS pathogenesis. Taken together, these studies should significantly extend our understanding of this neurodegenerative disorder and provide important information on the future selection of appropriate candidate therapeutic targets.

Research Signature Theme:

Aging, Genetics, and Social Science