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Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models

Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian...

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Autores principales: Kandasamy, Lenin C, Tsukamoto, Mina, Banov, Vitaliy, Tsetsegee, Sambuu, Nagasawa, Yutaro, Kato, Mitsuhiro, Matsumoto, Naomichi, Takeda, Junji, Itohara, Shigeyoshi, Ogawa, Sonoko, Young, Larry J, Zhang, Qi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161520/
https://www.ncbi.nlm.nih.gov/pubmed/33607654
http://dx.doi.org/10.1093/hmg/ddab052
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author Kandasamy, Lenin C
Tsukamoto, Mina
Banov, Vitaliy
Tsetsegee, Sambuu
Nagasawa, Yutaro
Kato, Mitsuhiro
Matsumoto, Naomichi
Takeda, Junji
Itohara, Shigeyoshi
Ogawa, Sonoko
Young, Larry J
Zhang, Qi
author_facet Kandasamy, Lenin C
Tsukamoto, Mina
Banov, Vitaliy
Tsetsegee, Sambuu
Nagasawa, Yutaro
Kato, Mitsuhiro
Matsumoto, Naomichi
Takeda, Junji
Itohara, Shigeyoshi
Ogawa, Sonoko
Young, Larry J
Zhang, Qi
author_sort Kandasamy, Lenin C
collection PubMed
description Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities.
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spelling pubmed-81615202021-06-02 Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models Kandasamy, Lenin C Tsukamoto, Mina Banov, Vitaliy Tsetsegee, Sambuu Nagasawa, Yutaro Kato, Mitsuhiro Matsumoto, Naomichi Takeda, Junji Itohara, Shigeyoshi Ogawa, Sonoko Young, Larry J Zhang, Qi Hum Mol Genet General Article Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities. Oxford University Press 2021-02-19 /pmc/articles/PMC8161520/ /pubmed/33607654 http://dx.doi.org/10.1093/hmg/ddab052 Text en © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle General Article
Kandasamy, Lenin C
Tsukamoto, Mina
Banov, Vitaliy
Tsetsegee, Sambuu
Nagasawa, Yutaro
Kato, Mitsuhiro
Matsumoto, Naomichi
Takeda, Junji
Itohara, Shigeyoshi
Ogawa, Sonoko
Young, Larry J
Zhang, Qi
Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
title Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
title_full Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
title_fullStr Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
title_full_unstemmed Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
title_short Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
title_sort limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161520/
https://www.ncbi.nlm.nih.gov/pubmed/33607654
http://dx.doi.org/10.1093/hmg/ddab052
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