Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
Spatiotemporal Tumor Heterogeneity, German Cancer Consortium (DKTK), Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany.
Nat Commun. 2024 May 15;15(1):4120. doi: 10.1038/s41467-024-48195-3.
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.
5q 相关脊髓性肌萎缩症（SMA）是一种由运动神经元 1 （SMN1）基因突变引起的运动神经元疾病。适应性免疫可能像其他运动神经元疾病一样导致 SMA，但机制仍不清楚。反义治疗药物 nusinersen 可增强 SMN2 的表达，使 SMA 患者受益。在这里，我们纵向研究了 SMA 和 nusinersen 对脑脊液（CSF）中局部免疫反应的影响 - 这是中枢神经系统实质的替代物。单细胞转录组学（SMA：N = 9 与对照：N = 9）显示未经治疗的 SMA CSF 中 NK 细胞和 CD8 + T 细胞扩增，表现出激活和脱颗粒标志物。与多重免疫组化相结合的空间转录组学阐明了近神经细胞溶解运动神经元的细胞毒性（N = 4）。在接受 nusinersen 治疗后，CSF 显示出未改变的蛋白/转录谱。这些发现强调了细胞毒性在 SMA 发病机制中的作用，并提出了它作为一种治疗靶点。我们的研究揭示了细胞介导的细胞毒性作为运动神经元疾病的共同特征，表明其具有更广泛的影响。
