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

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, Christopher Nelke, Jens T. Siveke, Tobias Ruck, Luisa Klotz, Carmen Haider, Romana Höftberger, Christoph Kleinschnitz, Heinz Wiendl, Tim Hagenacker () and Gerd Meyer zu Horste ()
Additional contact information
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
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
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
Tobias Ruck: Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Luisa Klotz: University Hospital Münster
Carmen Haider: Medical University of Vienna
Romana Höftberger: 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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48195-3

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