Project 1- CGG repeats as pathogenic driver and therapeutic target

Project 1 Abstract: Transcribed CGG repeat expansions in FMR1 cause Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) - an age-related neurodegenerative disorder characterized by gait imbalance, action tremors and dementia. Work to date has focused primarily on two potential underlying gain-of-function molecular mechanisms of disease: CGG repeat-containing mRNAs that bind to and sequester specific RNA binding proteins (CGG RNA toxicity) and repeat associated non-AUG (RAN) translation of the CGG repeats into polyglycine-containing proteins that contribute to inclusion formation in both patient samples and model systems. Exactly how each of these processes contribute to neurodegeneration and what role other factors might play in pathogenesis are critical unanswered questions in the field. Additionally, we lack tools to determine which premutation repeat carriers will manifest disease, which prevents us from intervening in patients prior to symptom onset – a potentially critical window for effective therapies. In this project, we will delineate how CGG repeat-associated toxicity drives neurodegeneration in FXTAS. Based on our preliminary data across multiple model systems, we propose that CGG repeats as both RNA and RAN translated products interact synergistically to activate neurodegenerative cascades that drive disease pathogenesis. This hypothesis implies that interventions that target either mechanism or the interplay between them should mitigate disease processes if applied early enough in FXTAS. We will assess this hypothesis using established complementary rodent and human model systems aligned with new tools and assays that will allow for targeted intervention. We will also assess whether the formation of ubiquitinated inclusions can serve as a trackable marker of disease. These studies will provide critical insights into the toxic mechanisms by which CGG repeats elicit FXTAS while assessing rational therapeutic approaches and a novel potential disease biomarker.