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Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a su...

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Autores principales: Winkler, Manuel, Biswas, Siladitta, Berger, Stefan M., Küchler, Moritz, Preisendörfer, Laurens, Choo, Myeongjeong, Früh, Simon, Rem, Pascal D., Enkel, Thomas, Arnold, Bernd, Komljenovic, Dorde, Sticht, Carsten, Goerdt, Sergij, Bettler, Bernhard, von Bohlen und Halbach, Oliver, Bartsch, Dusan, Géraud, Cyrill
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577901/
https://www.ncbi.nlm.nih.gov/pubmed/31511635
http://dx.doi.org/10.1038/s41380-019-0519-9
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author Winkler, Manuel
Biswas, Siladitta
Berger, Stefan M.
Küchler, Moritz
Preisendörfer, Laurens
Choo, Myeongjeong
Früh, Simon
Rem, Pascal D.
Enkel, Thomas
Arnold, Bernd
Komljenovic, Dorde
Sticht, Carsten
Goerdt, Sergij
Bettler, Bernhard
von Bohlen und Halbach, Oliver
Bartsch, Dusan
Géraud, Cyrill
author_facet Winkler, Manuel
Biswas, Siladitta
Berger, Stefan M.
Küchler, Moritz
Preisendörfer, Laurens
Choo, Myeongjeong
Früh, Simon
Rem, Pascal D.
Enkel, Thomas
Arnold, Bernd
Komljenovic, Dorde
Sticht, Carsten
Goerdt, Sergij
Bettler, Bernhard
von Bohlen und Halbach, Oliver
Bartsch, Dusan
Géraud, Cyrill
author_sort Winkler, Manuel
collection PubMed
description Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABA(B) receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.
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spelling pubmed-75779012020-11-02 Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior Winkler, Manuel Biswas, Siladitta Berger, Stefan M. Küchler, Moritz Preisendörfer, Laurens Choo, Myeongjeong Früh, Simon Rem, Pascal D. Enkel, Thomas Arnold, Bernd Komljenovic, Dorde Sticht, Carsten Goerdt, Sergij Bettler, Bernhard von Bohlen und Halbach, Oliver Bartsch, Dusan Géraud, Cyrill Mol Psychiatry Article Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABA(B) receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling. Nature Publishing Group UK 2019-09-11 2020 /pmc/articles/PMC7577901/ /pubmed/31511635 http://dx.doi.org/10.1038/s41380-019-0519-9 Text en © The Author(s) 2019 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/.
spellingShingle Article
Winkler, Manuel
Biswas, Siladitta
Berger, Stefan M.
Küchler, Moritz
Preisendörfer, Laurens
Choo, Myeongjeong
Früh, Simon
Rem, Pascal D.
Enkel, Thomas
Arnold, Bernd
Komljenovic, Dorde
Sticht, Carsten
Goerdt, Sergij
Bettler, Bernhard
von Bohlen und Halbach, Oliver
Bartsch, Dusan
Géraud, Cyrill
Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
title Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
title_full Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
title_fullStr Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
title_full_unstemmed Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
title_short Pianp deficiency links GABA(B) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
title_sort pianp deficiency links gaba(b) receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577901/
https://www.ncbi.nlm.nih.gov/pubmed/31511635
http://dx.doi.org/10.1038/s41380-019-0519-9
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