Department of Cell Biology, Neurobiology & Anatomy.
Department of Anesthesiology; and.
JCI Insight. 2024 Mar 7;9(8):e172869. doi: 10.1172/jci.insight.172869.
Patients with Fabry disease suffer from chronic debilitating pain and peripheral sensory neuropathy with minimal treatment options, but the cellular drivers of this pain are unknown. Here, we propose a mechanism we believe to be novel in which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observed in a genetic rat model of Fabry disease. Using in vivo and in vitro electrophysiological recordings, we demonstrated that Fabry rat sensory neurons exhibited pronounced hyperexcitability. Schwann cells probably contributed to this finding because application of mediators released from cultured Fabry Schwann cells induced spontaneous activity and hyperexcitability in naive sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells released elevated levels of the protein p11 (S100A10), which induced sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media caused hyperpolarization of neuronal resting membrane potentials, indicating that p11 may contribute to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that sensory neurons from rats with Fabry disease exhibit hyperactivity caused in part by Schwann cell release of the protein p11.
法布瑞病患者患有慢性衰弱性疼痛和周围感觉神经病，治疗选择有限，但这种疼痛的细胞驱动因素尚不清楚。在这里，我们提出了一个我们认为是新颖的机制，即在法布瑞病的遗传大鼠模型中，施万细胞和感觉神经元之间的信号改变导致了我们观察到的周围感觉神经功能障碍。通过体内和体外电生理记录，我们证明了法布瑞病大鼠感觉神经元表现出明显的过度兴奋。施万细胞可能对此发现有贡献，因为培养的法布瑞施万细胞释放的介质的应用诱导了幼稚感觉神经元的自发性活动和过度兴奋。我们使用蛋白质组学分析检查了潜在的致痛介质，发现法布瑞施万细胞释放高水平的蛋白 p11（S100A10），诱导感觉神经元过度兴奋。从法布瑞施万细胞培养基中去除 p11 导致神经元静息膜电位的超极化，表明 p11 可能导致法布瑞施万细胞引起的神经元过度兴奋。这些发现表明，法布瑞病大鼠的感觉神经元表现出过度活跃，部分原因是施万细胞释放蛋白 p11。
