Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment

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 expr...

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Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; p. 4120
Main Authors:	Lu, I-Na, Cheung, Phyllis Fung-Yi, Heming, Michael, Thomas, Christian, Giglio, Giovanni, Leo, Markus, Erdemir, Merve, Wirth, Timo, König, Simone, Dambietz, Christine A., Schroeter, Christina B., Nelke, Christopher, Siveke, Jens T., Ruck, Tobias, Klotz, Luisa, Haider, Carmen, Höftberger, Romana, Kleinschnitz, Christoph, Wiendl, Heinz, Hagenacker, Tim, Meyer zu Horste, Gerd
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15-05-2024 Nature Publishing Group Nature Portfolio
Subjects:	38/91 631/378/371 692/699/375/1917 82/51 82/58 Adaptive immunity Antisense therapy Atrophy Brain Brain - drug effects Brain - pathology CD8 antigen CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology Central nervous system Cerebrospinal fluid Child Child, Preschool Cytotoxicity Cytotoxicity, Immunologic - drug effects Degranulation Female Health services Humanities and Social Sciences Humans Immunohistochemistry Infant Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Lymphocytes Lymphocytes T Male Motor neurons Motor Neurons - drug effects Motor Neurons - metabolism Motor Neurons - pathology multidisciplinary Multiplexing Muscular Atrophy, Spinal - drug therapy Muscular Atrophy, Spinal - genetics Muscular Atrophy, Spinal - pathology Natural killer cells Oligonucleotides Parenchyma Pathogenesis Science Science (multidisciplinary) Single-Cell Analysis SMN protein Spinal muscular atrophy Survival of Motor Neuron 1 Protein - genetics Survival of Motor Neuron 1 Protein - metabolism Survival of Motor Neuron 2 Protein - genetics Therapeutic targets Toxicity Transcriptome Transcriptomics
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Summary:	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. Cell-mediated cytotoxicity observed in untreated SMA patients’ CSF and brain parenchyma. Spatial transcriptomic and multiplex immunohistochemistry linked cytotoxicity near affected motoneurons. Nusinersen treatment showed no impact on this profile.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-48195-3