Belančić Andrej, Janković Tamara, Gkrinia Elvira Meni Maria, Kristić Iva, Rajič Bumber Jelena, Rački Valentino, Pilipović Kristina, Vitezić Dinko, Mršić-Pelčić Jasenka
Department of Basic and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
Independent Researcher, 11741 Athens, Greece.
Neurol Int. 2025 Mar 13;17(3):41. doi: 10.3390/neurolint17030041.
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletions or mutations in the gene, leading to progressive motor neuron degeneration. While SMA has been classically viewed as a motor neuron-autonomous disease, increasing evidence indicates a significant role of glial cells-astrocytes, microglia, oligodendrocytes, and Schwann cells-in the disease pathophysiology. Astrocytic dysfunction contributes to motor neuron vulnerability through impaired calcium homeostasis, disrupted synaptic integrity, and neurotrophic factor deficits. Microglia, through reactive gliosis and complement-mediated synaptic stripping, exacerbate neurodegeneration and neuroinflammation. Oligodendrocytes exhibit impaired differentiation and metabolic support, while Schwann cells display abnormalities in myelination, extracellular matrix composition, and neuromuscular junction maintenance, further compromising motor function. Dysregulation of pathways such as NF-κB, Notch, and JAK/STAT, alongside the upregulation of complement proteins and microRNAs, reinforces the non-cell-autonomous nature of SMA. Despite the advances in SMN-restorative therapies, they do not fully mitigate glial dysfunction. Targeting glial pathology, including modulation of reactive astrogliosis, microglial polarization, and myelination deficits, represents a critical avenue for therapeutic intervention. This review comprehensively examines the multifaceted roles of glial cells in SMA and highlights emerging glia-targeted strategies to enhance treatment efficacy and improve patient outcomes.
脊髓性肌萎缩症（SMA）是一种由该基因的纯合缺失或突变引起的神经肌肉疾病，导致进行性运动神经元变性。虽然SMA传统上被视为一种运动神经元自主性疾病，但越来越多的证据表明神经胶质细胞（星形胶质细胞、小胶质细胞、少突胶质细胞和雪旺细胞）在该疾病的病理生理学中起重要作用。星形胶质细胞功能障碍通过钙稳态受损、突触完整性破坏和神经营养因子缺乏导致运动神经元易损性增加。小胶质细胞通过反应性胶质增生和补体介导的突触剥脱加剧神经退行性变和神经炎症。少突胶质细胞表现出分化和代谢支持受损，而雪旺细胞在髓鞘形成、细胞外基质组成和神经肌肉接头维持方面表现异常，进一步损害运动功能。NF-κB、Notch和JAK/STAT等信号通路的失调，以及补体蛋白和微小RNA的上调，强化了SMA的非细胞自主性。尽管在SMN恢复疗法方面取得了进展，但它们并不能完全减轻神经胶质功能障碍。针对神经胶质病理，包括调节反应性星形胶质增生、小胶质细胞极化和髓鞘形成缺陷，是治疗干预的关键途径。这篇综述全面研究了神经胶质细胞在SMA中的多方面作用，并强调了新兴的以神经胶质为靶点的策略，以提高治疗效果和改善患者预后。
