Waltz Tyler B, Chao Dongman, Prodoehl Eve K, Ehlers Vanessa L, Dharanikota Bhavya S, Dahms Nancy M, Isaeva Elena, Hogan Quinn H, Pan Bin, Stucky Cheryl L
bioRxiv. 2023 May 28:2023.05.26.542493. doi: 10.1101/2023.05.26.542493.
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 novel mechanism by which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observe in a genetic rat model of Fabry disease. Using and electrophysiological recordings, we demonstrate that Fabry rat sensory neurons exhibit pronounced hyperexcitability. Schwann cells likely contribute to this finding as application of mediators released from cultured Fabry Schwann cells induces spontaneous activity and hyperexcitability in naïve sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells release elevated levels of the protein p11 (S100-A10) which induces sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media causes hyperpolarization of neuronal resting membrane potential, indicating that p11 contributes to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that rats with Fabry disease exhibit sensory neuron hyperexcitability caused in part by Schwann cell release of the protein p11.
法布里病患者饱受慢性衰弱性疼痛和周围感觉神经病变之苦，而治疗选择极少，但这种疼痛的细胞驱动因素尚不清楚。在此，我们提出一种新机制，即雪旺细胞与感觉神经元之间信号传导的改变是我们在法布里病基因大鼠模型中观察到的周围感觉神经功能障碍的基础。通过体内和体外电生理记录，我们证明法布里大鼠感觉神经元表现出明显的过度兴奋性。雪旺细胞可能促成了这一发现，因为应用从培养的法布里病雪旺细胞释放的介质可诱导未成熟感觉神经元的自发活动和过度兴奋性。我们使用蛋白质组学分析检查了假定的致痛介质，发现法布里病雪旺细胞释放的蛋白质p11（S100 - A10）水平升高，该蛋白质可诱导感觉神经元过度兴奋性。从法布里病雪旺细胞培养基中去除p11会导致神经元静息膜电位超极化，表明p11促成了法布里病雪旺细胞引起的神经元过度兴奋性。这些发现表明，法布里病大鼠表现出的感觉神经元过度兴奋性部分是由雪旺细胞释放蛋白质p11所致。
