Journal Article

Prenatal SMN-dependent defects in translation uncover reversible primary cilia phenotypes in spinal muscular atrophy

Huang, Yu-Ting, Motyl, Anna A.L., Groen, Ewout J.N., Morris, Kimberley J., Gillingwater, Thomas H., Lai, Nicole C.H., Signoria, Ilaria, Pronot, Marie, Viero, Gabriella, Genovese, Federica, Sharma, Gaurav, Cousin, Michael A., Donzel, Deborah, Chaytow, Helena, Wishart, Thomas M., Paganin, Martina, Kline, Rachel A., Faller, Kiterie M.E.

2025

Overview

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of survival motor neuron (SMN) protein. Several therapeutic approaches boosting SMN are approved for human patients, delivering remarkable improvements in lifespan and symptoms. However, emerging phenotypes, including neurodevelopmental comorbidities, are being reported in some treated patients with SMA, indicative of alterations in brain development. Here, using a mouse model of severe SMA, we revealed an underlying neurodevelopmental phenotype in SMA where prenatal SMN-dependent defects in translation drove disruptions in nonmotile primary cilia across the central nervous system (CNS). Low levels of SMN caused widespread perturbations in translation at E14.5 targeting genes associated with primary cilia. The density of primary cilia in vivo, as well as cilial length in vitro, was significantly decreased in prenatal SMA mice. Proteomic analysis revealed downstream perturbations in primary cilia-regulated signaling pathways, including Wnt signaling. Cell proliferation was concomitantly reduced in the hippocampus of SMA mice. Prenatal transplacental therapeutic intervention with SMN-restoring risdiplam rescued primary cilia defects in SMA mouse embryos. Thus, SMN protein is required for normal cellular and molecular development of primary cilia in the CNS. Early, systemic treatment with SMN-restoring therapies can successfully target neurodevelopmental comorbidities in SMA.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Atrophy / Biology / Cell growth / Cell Proliferation / Cell survival / Central nervous system / Cilia / Cilia - genetics / Cilia - metabolism / Cilia - pathology / Comorbidity / Disease Models, Animal / Embryos / Female / Genes / Humans / Life span / Male / Mice / Morphology / Motor Neurons - metabolism / Muscular Atrophy, Spinal - genetics / Muscular Atrophy, Spinal - metabolism / Muscular Atrophy, Spinal - pathology / Neuromuscular diseases / Phenotype / Phenotypes / Pregnancy / Prenatal development / Protein Biosynthesis / Proteins / Proteomics / Ribonucleic acid / RNA / SMN protein / Spinal cord / Spinal muscular atrophy / Survival of Motor Neuron 1 Protein - genetics / Survival of Motor Neuron 1 Protein - metabolism / Translation / Wnt protein / Wnt Signaling Pathway