Formaggio Francesco, Pizzi Asia, Delprete Cecilia, Pasqualini Davide, Mataloni Isabella, Rimondini Roberto, Campolongo Ludovica, Donadio Vincenzo, Ghelli Anna Maria, Liguori Rocco, Caprini Marco
Laboratory of Cellular and Molecular Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
Laboratory of Cellular and Molecular Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
Neurobiol Dis. 2025 Sep;213:107000. doi: 10.1016/j.nbd.2025.107000. Epub 2025 Jun 13.
Neuropathic pain is a hallmark symptom in Fabry disease (FD), a hereditary X-linked lysosomal storage disorder caused by a reduced activity of α-galactosidase A (α-Gal A). The α-Gal A deficiency results in the progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in the body fluids and lysosomes of various cell types, including sensory ganglia. The FD neuropathy affects the small thinly myelinated Aδ fibers and unmyelinated C fibers leading to the loss of intra-epidermal neuronal terminations, along with altered thermal and mechanical perception. Lipid accumulation, such as Gb3 and lyso-Gb3, is implicated in various cellular dysfunctions, including the alteration of ionic currents. It has been shown that administration of Gb3 to human umbilical vein endothelial cells leads to the downregulation of the calcium (Ca)-activated K channel K3.1, whereas lyso-Gb3 evokes cytosolic Ca transients and an enhancement of voltage-activated Ca currents in murine dorsal root ganglia. Therefore, we examined the mechanism underlying Ca regulation in primary afferent neurons from the α-Gal A (-/0) mouse model. The obtained results suggest that other transport proteins participate in Ca homeostasis in FD and their dysfunction may be directly involved in nociception. In this context, plasma-membrane Ca ATPases exhibited reduced activity in FD, leading to an increased resting [Ca] in sensory neurons. The reduced activity was associated with a decrease of cytosolic pH which weakened the PMCA-dependent calcium extrusion. We finally evaluated the contribution of mitochondria to the Ca signalling and we observed impairment of the mitochondrial buffer capacity, as well as dysfunctional mitochondria and enhanced autophagy/mitophagy. These findings provide a basis for future insights into the alterations of calcium signalling underlying the onset of neuropathic symptoms in FD.
神经性疼痛是法布里病（FD）的一个标志性症状，法布里病是一种遗传性X连锁溶酶体贮积症，由α-半乳糖苷酶A（α-Gal A）活性降低引起。α-Gal A缺乏导致球三糖神经酰胺（Gb3）和球三糖鞘氨醇（lyso-Gb3）在包括感觉神经节在内的各种细胞类型的体液和溶酶体中进行性蓄积。FD神经病变会影响细小的有髓Aδ纤维和无髓C纤维，导致表皮内神经末梢丧失，同时热觉和机械觉也会改变。脂质蓄积，如Gb3和lyso-Gb3，与包括离子电流改变在内的各种细胞功能障碍有关。研究表明，将Gb3施用于人脐静脉内皮细胞会导致钙（Ca）激活的钾通道K3.1下调，而lyso-Gb3会引起小鼠背根神经节中的胞质Ca瞬变并增强电压激活的Ca电流。因此，我们研究了α-Gal A（-/-0）小鼠模型初级传入神经元中Ca调节的潜在机制。所得结果表明，其他转运蛋白参与了FD中的Ca稳态，其功能障碍可能直接与伤害感受有关。在这种情况下，质膜Ca ATP酶在FD中的活性降低，导致感觉神经元的静息[Ca]增加。活性降低与胞质pH值降低有关，这削弱了PMCA依赖的钙外排。我们最终评估了线粒体对Ca信号传导的贡献，观察到线粒体缓冲能力受损，以及线粒体功能障碍和自噬/线粒体自噬增强。这些发现为深入了解FD神经性症状发作背后的钙信号改变提供了基础。
