Molecular mechanisms of Friedreich’s ataxia and Fragile X syndrome

Around forty human diseases are associated with expanded repeat sequences. Among them are Friedreich ataxia and Fragile X syndrome. Friedreich’s ataxia (FRDA) is the most common inherited ataxia, characterised by progressive sensory ataxia, cardiomyopathy, diabetes, and premature death. FRDA is caused by an expanded GAA triplet repeat sequence in frataxin (FXN) gene, resulting in a transcriptional defect and consequently frataxin protein deficiency. Fragile X syndrome (FXS) is associated with expansion of more than 200 CGG repeats in the FMR1 gene, resulting in transcriptional silencing of FMR1 gene, leading to dramatic reduction of FMRP protein and causing intellectual disability in patients. The molecular mechanisms of FXN and FMR1 transcriptional silencing are not well understood. Recent evidence suggests that formation of repressive heterochromatin over the repeat regions plays a major role in this process. It has also been proposed that unusual DNA structures, such as RNA/DNA hybrids and triplex DNA, may form over the expanded repeats and contribute to gene silencing.

This project will employ various molecular and cell biology approaches to study the formation of unusual DNA structures over the expanded repeats of FXN and FMR1genes. We will investigate the interplay between these structures over expanded repeat regions and heterochromatin formation, transcriptional regulation and gene silencing in patient cells. We will employ genome-wide approaches to study the function of these structures in genome stability. Finally, we will also identify novel repeat-interacting proteins and study their function in FRDA and FXS pathology. The results generated in this project will help us to understand the molecular pathology of FRDA, FXS and other trinucleotide expansion disorders. In the long term the findings from this project will be essential for the development of new therapeutic approaches for FRDA and FXS disorders.