Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment.
Humans
Oligonucleotides
Muscular Atrophy, Spinal
/ drug therapy
Motor Neurons
/ drug effects
Killer Cells, Natural
/ immunology
Brain
/ pathology
Female
Male
Survival of Motor Neuron 2 Protein
/ genetics
CD8-Positive T-Lymphocytes
/ immunology
Survival of Motor Neuron 1 Protein
/ genetics
Single-Cell Analysis
Cytotoxicity, Immunologic
/ drug effects
Infant
Child, Preschool
Child
Transcriptome
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 May 2024
15 May 2024
Historique:
received:
15
06
2023
accepted:
24
04
2024
medline:
16
5
2024
pubmed:
16
5
2024
entrez:
15
5
2024
Statut:
epublish
Résumé
5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients. Here we have longitudinally investigated SMA and nusinersen effects on local immune responses in the cerebrospinal fluid (CSF) - a surrogate of central nervous system parenchyma. Single-cell transcriptomics (SMA: N = 9 versus Control: N = 9) reveal NK cell and CD8+ T cell expansions in untreated SMA CSF, exhibiting activation and degranulation markers. Spatial transcriptomics coupled with multiplex immunohistochemistry elucidate cytotoxicity near chromatolytic motoneurons (N = 4). Post-nusinersen treatment, CSF shows unaltered protein/transcriptional profiles. These findings underscore cytotoxicity's role in SMA pathogenesis and propose it as a therapeutic target. Our study illuminates cell-mediated cytotoxicity as shared features across motoneuron diseases, suggesting broader implications.
Identifiants
pubmed: 38750052
doi: 10.1038/s41467-024-48195-3
pii: 10.1038/s41467-024-48195-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4120Informations de copyright
© 2024. The Author(s).
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