Pathogenic Mechanisms in Fragile X Tremor Ataxia Syndrome

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DESCRIPTION (provided by applicant): Fragile X Tremor Ataxia Syndrome (FXTAS) is a common erited 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 drosophila 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 determine the alternative transcriptome profile of these human FXTAS neurons to address the hypothesis that sequestration of RNA binding proteins in FXTAS leads to aberrant mRNA splicing. Taken together, these studies should significantly extend our understanding of this neurodegenerative disorder and assist in identification appropriate candidate therapeutic targets. PUBLIC HEALTH RELEVANCE: Fragile X Tremor Ataxia syndrome (FXTAS) is a common inherited rodegenerative disorder that causes difficulties with walking, shaking of the limbs and dementia in older men. Our work proposes to test the idea that the genetic cause of FXTAS leads to neuronal death by two overlapping mechanisms: it increases the transcription of the mutant gene into RNA and it makes that RNA toxic to neurons, such that problems develop with the way these cells process and degrade other RNAs and proteins. To test our hypothesis we will utilize a fruit fly model of the disorder and we will also derive inducible pluripotent stem cells from patients with the disease so that we can study human derived neurons with the causative mutation. Taken together, we feel these studies will tell us a lot about what causes FXTAS and what we need to do to develop treatments for it.