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Sars Centre Guest Seminar Series
Srinivasa Subramaniam, University of Florida
Srinivasa Subramaniam, Associate professor, Department of Neuroscience, UF Scripps Biomedical Research at the University of Florida will present his talk: "Decoding hurdles in Huntington disease".
A ribosome typically moves at a particular rate on a given mRNA transcript to decode the nucleic acid information required to synthesize proteins. The speed and directionality of the ribosome movements during mRNA translation are determined by the mRNA sequence and structure and by various decoding factors. However, the molecular mechanisms of this remarkable movement during protein synthesis, or its relevance in brain disorders, remain unknown. Recent studies have indicated that defects in protein synthesis occur in various neurodegenerative diseases, but the mechanistic details are unclear. Huntington disease (HD) is caused by an expanded polyglutamine mutation in the huntingtin (mHTT), promoting prominent atrophy in the striatum and subsequent psychiatric, cognitive, and choreiform movements. We found that mHTT promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells. Depleting mHTT enhances protein synthesis and increases the speed of ribosomal translocation, while mHTT directly inhibits protein synthesis in vitro. We found interactions of ribosomal proteins and translating ribosomes with mHTT. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicates a widespread shift in ribosome occupancy toward the 5’ and 3’ end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. Ribo-seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (OXPHOS). By contrast, ribosome occupancy of mitochondrially encoded OXPHOS mRNAs was dramatically increased. Thus, mHTT impedes ribosomal translocation during translation elongation, regulates the translation of the mitochondrial OXPHOS transcripts, and influences HD pathogenesis. The work describing this work has been published in journals and preprint server.
