Neural Injury Group, Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
Cell Rep Med. 2021 Jul 21;2(7):100345. doi: 10.1016/j.xcrm.2021.100345. eCollection 2021 Jul 20.
Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in the or sub-units of the enzyme serine palmitoyltransferase, resulting in the production of toxic 1-deoxysphingolipid bases (DSBs). We used induced pluripotent stem cells (iPSCs) from patients with HSN1 to determine whether endogenous DSBs are neurotoxic, patho-mechanisms of toxicity and response to therapy. HSN1 iPSC-derived sensory neurons (iPSCdSNs) endogenously produce neurotoxic DSBs. Complex gangliosides, which are essential for membrane micro-domains and signaling, are reduced, and neurotrophin signaling is impaired, resulting in reduced neurite outgrowth. In HSN1 myelinating cocultures, we find a major disruption of nodal complex proteins after 8 weeks, which leads to complete myelin breakdown after 6 months. HSN1 iPSC models have, therefore, revealed that mutation alters lipid metabolism, impairs the formation of complex gangliosides, and reduces axon and myelin stability. Many of these changes are prevented by l-serine supplementation, supporting its use as a rational therapy.
遗传性感觉神经病 1 型（HSN1）是由丝氨酸棕榈酰转移酶的亚基 或 突变引起的，导致产生毒性 1-脱氧鞘氨醇脂质基底（DSBs）。我们使用 HSN1 患者的诱导多能干细胞（iPSC）来确定内源性 DSB 是否具有神经毒性、毒性的发病机制以及对治疗的反应。HSN1 iPSC 来源的感觉神经元（iPSCdSNs）内源性产生神经毒性 DSB。对于膜微区和信号转导至关重要的复杂神经节苷脂减少，神经营养因子信号转导受损，导致轴突生长减少。在 HSN1 髓鞘共培养物中，我们发现 8 周后节点复合物蛋白发生重大破坏，导致 6 个月后完全髓鞘破坏。因此，HSN1 iPSC 模型表明， 突变改变了脂质代谢，破坏了复杂神经节苷脂的形成，降低了轴突和髓鞘的稳定性。许多这些变化可以通过 l-丝氨酸补充来预防，支持其作为合理治疗方法的使用。
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