Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies

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.

Automated summary

Ciliopathies are a class of genetic diseases that cause dysfunction in cilia in multiple organ systems, including the olfactory system. This study investigates the mechanism behind the reduction of olfactory cilia in ciliopathy Bardet-Biedl syndrome (BBS) and finds that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and F-actin play important roles in cilia shortening. The researchers successfully restored cilia length and rescued odor detection and perception in BBS using a gene therapeutic approach. These findings provide valuable insights for the treatment of ciliopathies.