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Principal Investigator: Hannah Shorrock
Organization: STATE UNIVERSITY OF NEW YORK AT ALBANY
Fiscal Year: 2024
Award: $99,246
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Biology><Body Tissues><CAG repeat><CAG trinucleotide repeat><CRISPR><CRISPR/Cas system><Cell Line><CellLine><Clustered Regularly Interspaced Short Palindromic Repeats><Coupled><Data><Detection><Disease><Disorder><Functional RNA><Genetic><Genetics-Mutagenesis><Goals><Human><Human Genome><Immunoblotting><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Induced pluripotent stem cell derived neurons><Initiation Codon><Initiation Factors><Initiator Codon><Knowledge><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Methods><Microsatellite Markers><Microsatellite Repeats><Microsatellites><Modeling><Modern Man><Molecular><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Mutagenesis><Mutagenesis Molecular Biology><Nervous System Diseases><Nervous System Disorder><Neurologic Disorders><Neurological Disorders><Neuron from iPSC><Neuron from induced pluripotent stem cells><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Pathogenesis><Pathogenicity><Peptide Initiation Factors><Play><Poly Q><Process><Production><Proteins><Proteome><RNA><RNA Gene Products><Reading Frames><Reporter><Research><Ribonucleic Acid><Ribosomes><Role><Sedimentation process><Short interfering RNA><Small Interfering RNA><Start Codon><Strains Cell Lines><Structure><System><TC4 Protein><Testing><Therapeutic><Therapeutic Intervention><Tissues><Transcript><Translation Initiation Factor><Translational Initiation Factor><Translations><Treatment Efficacy><Untranslated RNA><Western Blotting><Western Immunoblotting><comparative><cultured cell line><design><designing><develop therapy><disease model><disorder model><genome scale><genome wide screen><genome-wide><genomewide><human whole genome><iPS neurons><iPSC derived-neurons><induced pluripotent stem cell neurons><innovate><innovation><innovative><interest><intervention development><intervention efficacy><intervention therapy><molecular modeling><neurological disease><neurons derived from induced pluripotent stem cells><noncoding><novel><permissiveness><polyQ><polyglutamine><polysome profiling><protein blotting><ran GTP-Binding Protein><ran Protein><ras-Related Nuclear Protein><sedimentation><siRNA><social role><therapeutic efficacy><therapy development><therapy efficacy><translation><translation factor><treatment development>