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

Genovese, F, Huang, Y-T, Motyl, AAL, Paganin, M, Sharma, G, Signoria, I, Donzel, D, Lai, NCH, Pronot, M, Kline, RA, Chaytow, H, Morris, KJ, Faller, KME, Wishart, TM ORCID: https://orcid.org/0000-0002-1973-6654, Groen, EJN, Cousin, MA, Viero, G and Gillingwater, TH, 2025. Prenatal SMN-dependent defects in translation uncover reversible primary cilia phenotypes in spinal muscular atrophy. JCI Insight. ISSN 2379-3708

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Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of 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 SMA patients, indicative of alterations in brain development. Here, using a mouse model of severe SMA, we revealed an underlying neurodevelopmental phenotype in SMA where
30 prenatal SMN-dependent defects in translation drove disruptions in non-motile primary cilia across the central nervous system (CNS). Low levels of SMN caused widespread perturbations in translation at embryonic day (E) 14.5 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 signalling pathways, including Wnt signalling. 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.

Item Type:	Journal article
Publication Title:	JCI Insight
Creators:	Genovese, F., Huang, Y.-T., Motyl, A.A.L., Paganin, M., Sharma, G., Signoria, I., Donzel, D., Lai, N.C.H., Pronot, M., Kline, R.A., Chaytow, H., Morris, K.J., Faller, K.M.E., Wishart, T.M., Groen, E.J.N., Cousin, M.A., Viero, G. and Gillingwater, T.H.
Publisher:	American Society for Clinical Investigation
Date:	9 September 2025
ISSN:	2379-3708
Identifiers:	Number Type 2495111 Other 10.1172/jci.insight.192835 DOI
Rights:	© 2025, Genovese et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jeremy Silvester
Date Added:	25 Sep 2025 15:22
Last Modified:	25 Sep 2025 15:22
URI:	https://irep.ntu.ac.uk/id/eprint/54434

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