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 see...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-08-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.158736 |
| _version_ | 1797634368012812288 |
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| author | Chao Xie Julien C. Habif Kirill Ukhanov Cedric R. Uytingco Lian Zhang Robert J. Campbell Jeffrey R. Martens |
| author_facet | Chao Xie Julien C. Habif Kirill Ukhanov Cedric R. Uytingco Lian Zhang Robert J. Campbell Jeffrey R. Martens |
| author_sort | Chao Xie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:45Z |
| format | Article |
| id | doaj.art-76bac830a4af4234ad34b906b2c0346d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:45Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-76bac830a4af4234ad34b906b2c0346d2023-11-07T16:24:24ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-08-01715Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathiesChao XieJulien C. HabifKirill UkhanovCedric R. UytingcoLian ZhangRobert J. CampbellJeffrey R. MartensCiliopathies 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.https://doi.org/10.1172/jci.insight.158736Cell biologyGenetics |
| spellingShingle | Chao Xie Julien C. Habif Kirill Ukhanov Cedric R. Uytingco Lian Zhang Robert J. Campbell Jeffrey R. Martens Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies JCI Insight Cell biology Genetics |
| title | Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies |
| title_full | Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies |
| title_fullStr | Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies |
| title_full_unstemmed | Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies |
| title_short | Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies |
| title_sort | reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies |
| topic | Cell biology Genetics |
| url | https://doi.org/10.1172/jci.insight.158736 |
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