Friday, April 4, 2025
4/4/2025
Mechanistic Basis for Non-Canonical Translation in Neurological Disease - Project Summary CAG repeat expansion diseases are the most common class of microsatellite expansion disorders. While canonical translation of the CAG repeat leads to the production of polyglutamine proteins, these expansions can also undergo non-canonical repeat associated non-AUG (RAN) translation. In the later process, translation is initiated across multiple reading frames in the absence of AUG- or AUG-like start codons. While a few factors that influence either canonical translation across microsatellite expansions or RAN translation have been identified, our understanding of the underlying molecular mechanisms responsible for translation in multiple reading frames is extremely limited. Despite evidence that RNA structure plays a key role in RAN translation our knowledge of the structural features that facilitate RAN translation is extremely limited. To examine the role of RNA structure in non-canonical translation, I used a structure-forward approach to screen for multi-frame translation, through which I identified several long non-coding RNAs (lncRNAs) that support translation in multiple reading frames in the absence of both microsatellite repeat expansions and AUG-start codons. This data suggests multiple avenues for RNA transcripts to support multi-frame translation, which has important implications in biology, disease, and therapeutics. The overarching goal of this proposal is to determine the RNA structures, protein networks and therapeutically relevant modifiers that govern various forms of multi-frame translation (MFT). To determine the proportion of the human genome capable of undergoing MFT, I will utilize a novel MFT reporter system to perform a genome-wide screen. Utilising candidate MFT sequences and CAG repeat expansions along with my already identified MFT lncRNAs, I will determine the cellular RNA structures and protein factors that facilitate non-canonical multi-frame translation. I will also employ a first-of-its-kind strategy to identify novel, therapeutically relevant modifiers of co-occurring canonical and non-canonical translation in multiple reading frames. These studies will enable a better understanding of the mechanism of multi-frame translation and identify therapeutic strategies that have the potential to provide therapeutic efficacy across multiple CAG repeat expansion diseases and be applicable to a wider range of neurological diseases. Together this research provides an innovative approach to understand a novel paradigm for translation diversity and will enable a better understanding of disease pathogenesis in repeat expansion diseases as well as elucidating the aspects of MFT most suitable to therapeutic intervention.
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