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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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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. |
format | Online Article Text |
id | pubmed-8760065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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