Immune cell–specific SMN expression and sustained immune alterations in treated spinal muscular atrophy
Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus
Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus
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Research Article Immunology Muscle biology Neuroscience

Immune cell–specific SMN expression and sustained immune alterations in treated spinal muscular atrophy

Abstract

Mutations in the survival of motor neuron 1 (SMN1) can reduce functional SMN protein levels, which causes spinal muscular atrophy (SMA), a disease affecting the nervous system and peripheral tissues, including the immune system. Yet, SMN expression across immune cell subsets and the effect of SMN-modulating therapies on the immune system remain underexplored. We found that in neonatal mouse spleens, SMN expression was highest in B cells, and was massively reduced in SMA mice. In human PBMCs from adults, DCs and monocytes expressed the highest SMN levels, whereas patients with SMA showed reduced DC frequencies and increased B cell frequencies. Patients receiving systemic versus CNS-restricted therapy showed similar differences in immune cell composition and SMN expression levels. Similarly, an exploratory cohort including untreated patients did not show a substantial treatment-specific effect relative to controls. To assess the effect of differentiation on SMN, we analyzed PMA-treated THP-1 cells and found enhanced aberrant SMN splicing and increased SMN+ Cajal bodies. SMN levels varied across immune cell types, and reduced SMN levels were associated with altered immune cell composition. Immune alterations and decreased SMN levels were observed in both treated and untreated patients with SMA and may have contributed to dysfunctions of the immune system.

Authors

Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus

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Figure 4

SMN expression is reduced across all immune cell types of treated adult SMA patients.

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SMN expression is reduced across all immune cell types of treated adult ...
(A) Quantification of gMFI SMN protein expression across immune cell clusters in healthy controls and patients with SMA. Each data point represents an individual biological replicate, and data represent the mean ± SD. Statistical comparisons between groups were performed for each cell type using an unpaired, 2-tailed Student’s t test without multiple comparisons. *P < 0.05. Samples were acquired in 2 independent experiments performed on consecutive days. Statistical analyses include all samples from both experiments, whereas the histogram overlays and UMAP visualizations shown in B–E are representative of 1 experiment. (B) UMAP visualization of SMN expression in CD45+ immune cells from a representative healthy control dataset, displayed using a heatmap color scale. SMN expression is shown as the gMFI. (C) Histogram overlays showing total SMN protein expression levels across all immune cells in PBMCs from healthy controls (n = 7, left) and in individual immune cell clusters of 1 representative control sample (right), colored according to cluster identity. (D) UMAP visualization of SMN expression in immune cells from patients with SMA, using the same heatmap scale as in B. (E) Histogram overlays showing total SMN protein expression in PBMCs from patients with SMA (n = 13, left) and in individual immune cell clusters of 1 representative risdiplam-treated patient, matching the cluster identities shown in C. Histograms were normalized independently for each subpanel, with the y axis representing the percentage of the maximum bin count within that subpanel (for comparisons of immune cell frequencies between subpanels, refer to Figure 3). The x axis shows SMN expression on a common scale across all panels. Vertical reference lines indicate identical x values for better comparison between control and SMA samples.