Prenatal SMN-dependent defects in translation uncover reversible primary cilia phenotypes in a mouse model of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a rare inherited neuromuscular disease with an incidence of around one in every 10,000 live births. In most patients, SMA is caused by mutations in the survival motor neuron 1 gene (SMN1), resulting in insufficient production of full-length, functional SMN protein. The SMN protein is dynamically regulated during development, where high levels of SMN expression during embryogenesis undergo a significant reduction after birth, suggesting an important role for SMN prenatally. SMN has also been shown to be a ribosome-associated protein that plays a crucial role in translation and ribosome biology. Therefore, when SMN is depleted, widespread perturbations of protein synthesis occur in SMA. Several therapeutic approaches aimed at boosting SMN are now approved for use in human patients, leading to significant improvements in lifespan and symptom severity. However, new and unexpected phenotypes are being reported in treated SMA patients, including significant neurodevelopmental alterations in some individuals, indicative of changes in brain development. In this thesis, I use a mouse model of severe SMA to explore the prenatal development of the central nervous system (CNS). Using a combination of morphological and molecular analyses, I reveal neurodevelopmental defects in SMA embryos and demonstrate that these changes are accompanied by widespread perturbations in translation.

Furthermore, by performing network analysis of the genes presenting with alterations in ribosome occupancy, I show the involvement in processes related to primary cilia. Assessments of primary cilia in the CNS in vivo and in primary neuronal cultures in vitro confirmed the presence of a primary cilia phenotype in SMA. Finally, to demonstrate that this observed novel phenotype is SMN-dependent, and amenable to therapeutic intervention, in this work I show that prenatal transplacental treatment with risdiplam, an approved SMN-restoring drug, can rescue primary cilia defects in SMA mouse embryos. Using these approaches, I unveil that SMN protein is necessary for the normal cellular and molecular development of primary cilia in the CNS, and that prenatal treatment with SMN-restoring therapies can address neurodevelopmental phenotypes in SMA.