Department of Human Molecular Genetics and Biochemestry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel.
PLoS One. 2019 Mar 19;14(3):e0211602. doi: 10.1371/journal.pone.0211602. eCollection 2019.
Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5' splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients.
家族性自主神经异常症（FD）是一种常染色体隐性先天性神经病，由 IKBKAP 基因内含子 20 的 5' 剪接位点的点突变引起。这种突变会降低 IKAP 蛋白的产生，而增加全长 IKBKAP 转录本水平的治疗方法可能具有治疗价值。我们之前发现，磷脂酰丝氨酸（PS），一种 FDA 批准的食品补充剂，可提高来自 FD 患者的细胞中的 IKAP 水平。在这里，我们证明了 PS 与激动素或 PS 与组蛋白去乙酰化酶抑制剂曲古抑菌素 A（TSA）联合治疗来自 FD 患者的细胞，与每种药物单独治疗相比，可使 IKAP 水平显著升高。这表明这些化合物影响不同的途径。我们还发现普里多宾可提高来自 FD 患者的细胞中 IKAP 的产生。普里多宾与激动素或 TSA 联合使用时，对 IKAP 水平有相加作用，但与 PS 无相加作用；表明 PS 和普里多宾通过相同的机制影响 IKBKAP 水平。事实上，我们证明 PS 和普里多宾的作用是通过 sigma-1 受体介导的 BDNF 信号通路的激活。具有不同机制的这些药物的联合治疗可能对 FD 患者有益。
