Bardet–Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2^−/− cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS. Consequently, we tested whether BBS pathology in Bbs2^−/− mice can be reversed by targeting the underlying ciliary defect via reduction of GSL metabolism. Inhibition of GSL synthesis with the glucosylceramide synthase inhibitor Genz-667161 decreases the obesity, liver disease, retinal degeneration and olfaction defect in Bbs2^−/− mice. These effects are secondary to preservation of ciliary structure and signaling, and stimulation of cellular differentiation. In conclusion, reduction of GSL metabolism resolves the multi-organ pathology of Bbs2^−/− mice by directly preserving ciliary structure and function towards a normal phenotype. Since this approach does not rely on the correction of the underlying genetic mutation, it might translate successfully as a treatment for other ciliopathies.

中文翻译：

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纤毛结构和功能的矫正减轻了 Bardet-Biedl 综合征小鼠的多器官病理。

Bardet-Biedl 综合征 (BBS) 是一种影响多个器官的多效性常染色体隐性纤毛病。BBS 潜在疾病改善疗法的开发将需要同时针对多系统表现。在这里，我们首次表明单唾液酸二己糖神经节苷脂在Bbs2 ^-/-纤毛中积累，表明 BBS 中鞘糖脂 (GSL) 代谢受损。因此，我们测试了Bbs2 ^-/-小鼠的BBS 病理是否可以通过减少 GSL 代谢靶向潜在的纤毛缺陷来逆转。用葡糖神经酰胺合酶抑制剂 Genz-667161 抑制 GSL 合成可减少Bbs2 ^{-/- 中}的肥胖、肝病、视网膜变性和嗅觉缺陷老鼠。这些作用继发于纤毛结构和信号传导的保存以及细胞分化的刺激。总之，GSL 代谢的减少通过直接保持纤毛结构和功能向正常表型来解决Bbs2 ^-/-小鼠的多器官病理。由于这种方法不依赖于对潜在基因突变的纠正，因此它可能会成功地转化为其他纤毛病的治疗方法。