Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Xie, Chao, Habif, Julien C., Ukhanov, Kirill, Uytingco, Cedric R., Zhang, Lian, Campbell, Robert J., Martens, Jeffrey R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462494/
https://www.ncbi.nlm.nih.gov/pubmed/35771640
http://dx.doi.org/10.1172/jci.insight.158736
_version_ 1784787197791043584
author Xie, Chao
Habif, Julien C.
Ukhanov, Kirill
Uytingco, Cedric R.
Zhang, Lian
Campbell, Robert J.
Martens, Jeffrey R.
author_facet Xie, Chao
Habif, Julien C.
Ukhanov, Kirill
Uytingco, Cedric R.
Zhang, Lian
Campbell, Robert J.
Martens, Jeffrey R.
author_sort Xie, Chao
collection PubMed
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)P(2)], 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)P(2) and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P(2) 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)P(2)/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.
format Online
Article
Text
id pubmed-9462494
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-94624942022-09-13 Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies Xie, Chao Habif, Julien C. Ukhanov, Kirill Uytingco, Cedric R. Zhang, Lian Campbell, Robert J. Martens, Jeffrey R. JCI Insight Research Article 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)P(2)], 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)P(2) and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P(2) 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)P(2)/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. American Society for Clinical Investigation 2022-08-08 /pmc/articles/PMC9462494/ /pubmed/35771640 http://dx.doi.org/10.1172/jci.insight.158736 Text en © 2022 Xie et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Xie, Chao
Habif, Julien C.
Ukhanov, Kirill
Uytingco, Cedric R.
Zhang, Lian
Campbell, Robert J.
Martens, Jeffrey R.
Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies
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 Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462494/
https://www.ncbi.nlm.nih.gov/pubmed/35771640
http://dx.doi.org/10.1172/jci.insight.158736
work_keys_str_mv AT xiechao reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies
AT habifjulienc reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies
AT ukhanovkirill reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies
AT uytingcocedricr reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies
AT zhanglian reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies
AT campbellrobertj reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies
AT martensjeffreyr reversalofciliarymechanismsofdisassemblyrescuesolfactorydysfunctioninciliopathies