PDF(Pubmed)
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.
摘要：
5q相关的脊髓性肌萎缩症（SMA）是由存活运动神经元1（SMN1）基因突变引起的运动神经元疾病。如其他运动神经元疾病所述，适应性免疫可能有助于SMA，然而机制仍然难以捉摸。Nusinersen,反义治疗，增强SMN2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）局部免疫反应的影响-脑脊液是中枢神经系统实质的替代品。单细胞转录组学（SMA：N=9对对照：N=9）揭示了未处理的SMACSF中的NK细胞和CD8T细胞扩增，表现出活化和脱粒标记。空间转录组学与多重免疫组织化学联用可阐明色谱分解运动神经元附近的细胞毒性（N=4）。Nusinersen治疗后,CSF显示未改变的蛋白质/转录谱。这些发现强调了细胞毒性在SMA发病机制中的作用，并提出将其作为治疗靶点。我们的研究阐明了细胞介导的细胞毒性是运动神经元疾病的共同特征，暗示了更广泛的影响。
