Repeat associated non-AUG (RAN) proteins in FA: contribution to disease and therapeutic opportunities

This project aims to understand if repeat-associated non-AUG (RAN) translation, a process in which repeat expansions produce unexpected toxic repetitive proteins, contributes to FA, thus opening new avenues for therapeutic intervention. In 2011, the Ranum lab made the surprising discovery that repeat expansions produce unexpected toxic repetitive proteins without the canonical AUG start codon in a process called repeat-associated non-AUG (RAN ) translation. RAN proteins have been shown to be toxic to cells and to contribute to disease in other repeat expansion disorders like myotonic dystrophy type 2 and C9-ALS/FTD. Given that RAN proteins are found in a growing number of repeat expansion diseases, this raises the possibility that RAN proteins may be expressed from the FXN GAA•TTC expansion mutation and potentially contribute to FA. The Ranum lab recently developed antibodies that specifically recognize the repetitive sequences in RAN proteins and found that RAN aggregates accumulate in the cerebellum and spinal cord from FA (n>5) but not control (n>4) autopsy cases. This discovery creates an urgent need to understand how these proteins are produced and if they contribute to disease. The current project aims to address gaps in knowledge about the GAA•TTC expansion mutation, RAN translation, and whether toxic RAN proteins contribute to FA. The aims are structured to provide a comprehensive analysis of RAN proteins in human autopsy tissue and patient-derived models and examine the association between frataxin levels and FA RAN protein accumulation. Since the Ranum lab has successfully found a way to inhibit RAN translation, Dr. Romano will use genetic and pharmacological approaches to reduce RAN proteins in FA models to determine if lowering RAN proteins improves cellular FA phenotypes. The long-term goal of this project is to understand if and how RAN proteins contribute to FA and ultimately to generate new therapeutic treatment strategies for FA patients.