Antisense oligonucleotides treatment uncovers differences in the modulation of dysregulated intracellular pathways in Spinal Muscular Atrophy motoneurons.

Authors

Maria P Miralles, Isabel Gimenez-Fernandez, Maria Beltran, Alba Sansa, Laura Martínez-España, Jordi Calderó, Manuel Portero-Otín, Rosa M Soler, Ana Garcera

Published in

Cell death & disease. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Spinal Muscular Atrophy (SMA) is a neuromuscular genetic disorder resulting from the mutation or deletion of the Survival Motor Neuron 1 (SMN1) gene and the reduction of the Survival Motor Neuron (SMN) protein. As a result, SMN level in SMA depends on the almost identical copy gene SMN2, which produces a small amount of functional SMN due to a silent mutation in exon 7. SMN deficiency critically impairs spinal cord motoneuron (MN) function, causing progressive degeneration. Advances in SMA therapeutics have significantly improved clinical management and prognosis. However, therapeutic outcomes vary among SMA patients, resulting in broad heterogeneity in phenotypes and clinical trajectories; consequently, more focused investigation on the underlying disease mechanisms is essential. One of the FDA-approved treatments is nusinersen, an antisense oligonucleotide (ASO) designed to enhance SMN2 exon 7 splicing and increase SMN protein. The present study used non-SMA and SMA MNs differentiated from human induced Pluripotent Stem Cells (hiPSCs) to analyze the effect of a nusinersen-like ASO treatment on intracellular pathways altered in SMA MNs. ASO treatment efficiently increased SMN, prevented MN degeneration, and decreased apoptotic markers in SMA MNs. Furthermore, treatment increased Gemin3 protein and the NF-κB members, IKKβ and RelA. Nevertheless, ASO did not revert alterations of the autophagy markers LC3-II and p62/SQSTM1, and the calpain activation product α-fodrin 145/150 kDa. Our observations indicate that nusinersen-like ASO treatment might be insufficient to counteract the full spectrum of intracellular alterations occurring in SMN-reduced MNs. Therefore, supplementary compounds targeting these unrecovered pathways might supply additional protective effects on degenerating MNs.

PMID:
42443163
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.