Ribosomes have been put under spotlight as putative direct influencers of translation. An intriguing hypothesis is that ribosome composition is heterogeneous and can be modulated by protein composition, rRNA variants and ribosome-associated proteins (RAPs). However, the contribution of ribosome heterogeneity and ribosome-associated proteins in controlling translation and the contribution to disease development remain unclear.
Here, we used in vivo, in vitro and in cellulo models of disease coupled to positional analysis of ribosomes at single nucleotide resolution, proteomics, and structural analysis, to reveal at unprecedented detail the involvement of the Survival Motor Neuron protein (SMN), loss of which causes the neuromuscular disease spinal muscular atrophy (SMA), in ribosome functioning. Using cutting edge sequencing approaches complemented by biophysical and biochemical assays, we demonstrated that SMN binds to ribosomes (SMN-primed ribosomes) controlling the translation efficiency of a specific population of mRNAs. These SMN-specific transcripts are characterized by enrichment of translational enhancer sequences in the 5’UTR and rare codons at the beginning of their coding sequence. In addition, we identified pre-symptomatic and pre-natal defects in multiple tissues and mouse models of SMA that impact a plethora of biological processes. Our results not only expand our understanding of SMN biology and SMA disease pathogenesis but bring us in the unique position to move from fundamental and biology-based hypotheses to the development of second-generation therapies.
Introduction: Davide Scaglione, PhD - CEO- IGA Technology Services
Speaker: Gabriella Viero, PhD - Senior researcher- Institute of Biophysics CNR Italy