Department of Pharmacology and Therapeutics and.
Center for Smell and Taste, University of Florida College of Medicine, Gainesville, Florida, USA.
JCI Insight. 2022 Aug 8;7(15):e158736. doi: 10.1172/jci.insight.158736.
Ciliopathies are a class of genetic diseases resulting in cilia dysfunction in multiple organ systems, including the olfactory system. Currently, there are no available curative treatments for olfactory dysfunction and other symptoms in ciliopathies. The loss or shortening of olfactory cilia, as seen in multiple mouse models of the ciliopathy Bardet-Biedl syndrome (BBS), results in olfactory dysfunction. However, the underlying mechanism of the olfactory cilia reduction is unknown, thus limiting the development of therapeutic approaches for BBS and other ciliopathies. Here, we demonstrated that phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a phosphoinositide typically excluded from olfactory cilia, aberrantly redistributed into the residual cilia of BBS mouse models, which caused F-actin ciliary infiltration. Importantly, PI(4,5)P2 and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P2 by overexpression of inositol polyphosphate-5-phosphatase E (INPP5E) restored cilia length and rescued odor detection and odor perception in BBS. Together, our data indicate that PI(4,5)P2/F-actin-dependent cilia disassembly is a common mechanism contributing to the loss of olfactory cilia in BBS and provide valuable pan-therapeutic intervention targets for the treatment of ciliopathies.
纤毛病是一类遗传疾病，导致多个器官系统（包括嗅觉系统）的纤毛功能障碍。目前，对于纤毛病中的嗅觉功能障碍和其他症状还没有可行的治疗方法。纤毛病中嗅纤毛的缺失或缩短，如 Bardet-Biedl 综合征（BBS）多种小鼠模型所见，导致嗅觉功能障碍。然而，嗅纤毛减少的潜在机制尚不清楚，从而限制了 BBS 和其他纤毛病的治疗方法的发展。在这里，我们证明了磷脂酰肌醇 4,5-二磷酸[PI（4,5）P2]，一种通常从嗅觉纤毛中排除的磷酸肌醇，异常重新分布到 BBS 小鼠模型的残余纤毛中，导致 F-肌动蛋白纤毛内渗。重要的是，PI（4,5）P2 和 F-肌动蛋白对于嗅纤毛缩短是必需的。通过基因治疗方法，通过过度表达肌醇多磷酸-5-磷酸酶 E（INPP5E）水解 PI（4,5）P2，恢复了纤毛长度，并挽救了 BBS 中的气味检测和气味感知。总之，我们的数据表明，PI（4,5）P2/F-肌动蛋白依赖性纤毛解体是导致 BBS 中嗅觉纤毛丧失的共同机制，并为治疗纤毛病提供了有价值的泛治疗干预靶点。
