Gabriella Viero, Institute of Biophysics - CNR Unit, Trento

Friday, 6th October - h. 11:00
Seminars Room, NICO

Gabriella Viero
Institute of Biophysics, CNR Unit, Trento

On the unexpected role of SMN protein in controlling translation: implications for Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease caused by low levels of SMN protein. SMN undertakes various roles in the cytoplasm and co-sediments with polysomes, but the contribution of SMN/polysome crosstalk to disease pathogenesis has not never been established. Given SMN’s role in mRNA metabolism, and the intimate relationship between mRNA-decay and translation that converges on polysomes, we hypothesize that SMN plays a polysome-centered role in the pathogenesis of SMA.

To understand the role of SMN in translation, we investigated the consequences of low levels of SMN for translational regulation in vivo, using an established mouse model of SMA. We report for the first time widespread and robust perturbations in translation efficiency and mRNA recruitment on polysomes in pathologically relevant tissues at both early and late symptomatic stages, and show that decreased translation efficiencies are associated with SMA disease progression. Sequencing of mRNAs recruited on polysomes (POL-Seq) and ribosome protected fragments (RIBO-Seq) led to the identification of RNAs (coding and non-coding) that are differentially associated with polysomes in SMA. Polysome perturbations and subsequent translational defects were rescued by treatment with an antisense oligonucleotide (ASO) restoring SMN levels, indicating that these defects are both reversible and amenable to therapeutic intervention.

Host: Alessandro Vercelli