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

Author

Listed:
  • I-Na Lu

    (University Hospital Münster)

  • Phyllis Fung-Yi Cheung

    (Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
    University Hospital Essen, University of Duisburg-Essen
    Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen)

  • Michael Heming

    (University Hospital Münster)

  • Christian Thomas

    (University Hospital Münster)

  • Giovanni Giglio

    (Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
    University Hospital Essen, University of Duisburg-Essen
    Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen)

  • Markus Leo

    (University Hospital Essen)

  • Merve Erdemir

    (University Hospital Essen)

  • Timo Wirth

    (University Hospital Münster)

  • Simone König

    (University of Münster)

  • Christine A. Dambietz

    (University Hospital Münster)

  • Christina B. Schroeter

    (Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf)

  • Christopher Nelke

    (Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf)

  • Jens T. Siveke

    (Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen
    University Hospital Essen, University of Duisburg-Essen
    Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen)

  • Tobias Ruck

    (Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf)

  • Luisa Klotz

    (University Hospital Münster)

  • Carmen Haider

    (Medical University of Vienna
    Medical University of Vienna)

  • Romana Höftberger

    (Medical University of Vienna
    Medical University of Vienna)

  • Christoph Kleinschnitz

    (University Hospital Essen)

  • Heinz Wiendl

    (University Hospital Münster)

  • Tim Hagenacker

    (University Hospital Essen)

  • Gerd Meyer zu Horste

    (University Hospital Münster)

Abstract

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.

Suggested Citation

  • I-Na Lu & Phyllis Fung-Yi Cheung & Michael Heming & Christian Thomas & Giovanni Giglio & Markus Leo & Merve Erdemir & Timo Wirth & Simone König & Christine A. Dambietz & Christina B. Schroeter & Chris, 2024. "Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48195-3
    DOI: 10.1038/s41467-024-48195-3
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