An early Transcriptomic Investigation in Adult Patients with Spinal Muscular Atrophy Under Treatment with Nusinersen.
SMN1
SMN2
HT-NGS
Nusinersen
Spinal muscular atrophy (SMA)
mRNAs
miRNAs
Journal
Journal of molecular neuroscience : MN
ISSN: 1559-1166
Titre abrégé: J Mol Neurosci
Pays: United States
ID NLM: 9002991
Informations de publication
Date de publication:
26 Sep 2024
26 Sep 2024
Historique:
received:
27
04
2024
accepted:
17
07
2024
medline:
26
9
2024
pubmed:
26
9
2024
entrez:
26
9
2024
Statut:
epublish
Résumé
Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre-mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted "restored" at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis.
Identifiants
pubmed: 39325116
doi: 10.1007/s12031-024-02251-1
pii: 10.1007/s12031-024-02251-1
doi:
Substances chimiques
nusinersen
5Z9SP3X666
MicroRNAs
0
Oligonucleotides
0
Survival of Motor Neuron 2 Protein
0
Survival of Motor Neuron 1 Protein
0
SMN2 protein, human
0
SMN1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
89Subventions
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Organisme : Apulian Regional Council
ID : D.U.P. n.246/2019, D.D. n. 3 of 13 January 2021
Informations de copyright
© 2024. The Author(s).
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