Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation

Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms under...

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Autores principales: del Puerto, Ana, Pose-Utrilla, Julia, Simón-García, Ana, López-Menéndez, Celia, Jiménez, Antonio J., Porlan, Eva, Pajuelo, Luis S. M., Cano-García, Guillermo, Martí-Prado, Beatriz, Sebastián-Serrano, Álvaro, Sánchez-Carralero, Marina P., Cesca, Fabrizia, Schiavo, Giampietro, Ferrer, Isidro, Fariñas, Isabel, Campanero, Miguel R., Iglesias, Teresa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760065/
https://www.ncbi.nlm.nih.gov/pubmed/34002021
http://dx.doi.org/10.1038/s41380-021-01127-9
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author del Puerto, Ana
Pose-Utrilla, Julia
Simón-García, Ana
López-Menéndez, Celia
Jiménez, Antonio J.
Porlan, Eva
Pajuelo, Luis S. M.
Cano-García, Guillermo
Martí-Prado, Beatriz
Sebastián-Serrano, Álvaro
Sánchez-Carralero, Marina P.
Cesca, Fabrizia
Schiavo, Giampietro
Ferrer, Isidro
Fariñas, Isabel
Campanero, Miguel R.
Iglesias, Teresa
author_facet del Puerto, Ana
Pose-Utrilla, Julia
Simón-García, Ana
López-Menéndez, Celia
Jiménez, Antonio J.
Porlan, Eva
Pajuelo, Luis S. M.
Cano-García, Guillermo
Martí-Prado, Beatriz
Sebastián-Serrano, Álvaro
Sánchez-Carralero, Marina P.
Cesca, Fabrizia
Schiavo, Giampietro
Ferrer, Isidro
Fariñas, Isabel
Campanero, Miguel R.
Iglesias, Teresa
author_sort del Puerto, Ana
collection PubMed
description Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa (KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives.
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spelling pubmed-87600652022-01-26 Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation del Puerto, Ana Pose-Utrilla, Julia Simón-García, Ana López-Menéndez, Celia Jiménez, Antonio J. Porlan, Eva Pajuelo, Luis S. M. Cano-García, Guillermo Martí-Prado, Beatriz Sebastián-Serrano, Álvaro Sánchez-Carralero, Marina P. Cesca, Fabrizia Schiavo, Giampietro Ferrer, Isidro Fariñas, Isabel Campanero, Miguel R. Iglesias, Teresa Mol Psychiatry Article Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa (KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives. Nature Publishing Group UK 2021-05-17 2021 /pmc/articles/PMC8760065/ /pubmed/34002021 http://dx.doi.org/10.1038/s41380-021-01127-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
del Puerto, Ana
Pose-Utrilla, Julia
Simón-García, Ana
López-Menéndez, Celia
Jiménez, Antonio J.
Porlan, Eva
Pajuelo, Luis S. M.
Cano-García, Guillermo
Martí-Prado, Beatriz
Sebastián-Serrano, Álvaro
Sánchez-Carralero, Marina P.
Cesca, Fabrizia
Schiavo, Giampietro
Ferrer, Isidro
Fariñas, Isabel
Campanero, Miguel R.
Iglesias, Teresa
Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation
title Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation
title_full Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation
title_fullStr Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation
title_full_unstemmed Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation
title_short Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation
title_sort kidins220 deficiency causes ventriculomegaly via snx27-retromer-dependent aqp4 degradation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760065/
https://www.ncbi.nlm.nih.gov/pubmed/34002021
http://dx.doi.org/10.1038/s41380-021-01127-9
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