Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia

Hyperekplexia is a rare sensorimotor syndrome characterized by pathological startle reflex in response to unexpected trivial stimuli for which there is no specific treatment. Neonates suffer from hypertonia and are at high risk of sudden death due to apnea episodes. Mutations in the human SLC6A5 gen...

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Detalhes bibliográficos
Autores: de la Rocha Muñoz, Andrés, Melgarejo, Elena, Aragón, Carmen, López-Corcuera, Beatriz
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/268706
Acesso em linha:http://hdl.handle.net/10261/268706
Access Level:acceso abierto
Palavra-chave:Transport
Glycine
Hyperekplexia Mutation
Chemical chaperone
Calnexin
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spelling Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexiade la Rocha Muñoz, AndrésMelgarejo, ElenaAragón, CarmenLópez-Corcuera, BeatrizTransportGlycineHyperekplexia MutationChemical chaperoneCalnexinHyperekplexia is a rare sensorimotor syndrome characterized by pathological startle reflex in response to unexpected trivial stimuli for which there is no specific treatment. Neonates suffer from hypertonia and are at high risk of sudden death due to apnea episodes. Mutations in the human SLC6A5 gene encoding the neuronal glycine transporter GlyT2 may disrupt the inhibitory glycinergic neurotransmission and cause a presynaptic form of the disease. The phenotype of missense mutations giving rise to protein misfolding but maintaining residual activity could be rescued by facilitating folding or intracellular trafficking. In this report, we characterized the trafficking properties of two mutants associated with hyperekplexia (A277T and Y707C, rat numbering). Transporter molecules were partially retained in the endoplasmic reticulum showing increased interaction with the endoplasmic reticulum chaperone calnexin. One transporter variant had export difficulties and increased ubiquitination levels, suggestive of enhanced endoplasmic reticulum-associated degradation. However, the two mutant transporters were amenable to correction by calnexin overexpression. Within the search for compounds capable of rescuing mutant phenotypes, we found that the arachidonic acid derivative N-arachidonoyl glycine can rescue the trafficking defects of the two variants in heterologous cells and rat brain cortical neurons. N-arachidonoyl glycine improves the endoplasmic reticulum output by reducing the interaction transporter/calnexin, increasing membrane expression and improving transport activity in a comparable way as the well-established chemical chaperone 4-phenyl-butyrate. This work identifies N-arachidonoyl glycine as a promising compound with potential for hyperekplexia therapy.Spanish ‘Ministerio de Economía y Competitividad’, grant number SAF2017-84235-R (AEI/ FEDER, EU) to B.L.-C. and by institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSOMinisterio de Economía y Competitividad (España)Fundación Ramón ArecesBanco SantanderConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/268706reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1016/j.neuropharm.2021.108543Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2687062026-05-22T06:33:51Z
dc.title.none.fl_str_mv Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
title Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
spellingShingle Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
de la Rocha Muñoz, Andrés
Transport
Glycine
Hyperekplexia Mutation
Chemical chaperone
Calnexin
title_short Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
title_full Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
title_fullStr Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
title_full_unstemmed Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
title_sort Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
dc.creator.none.fl_str_mv de la Rocha Muñoz, Andrés
Melgarejo, Elena
Aragón, Carmen
López-Corcuera, Beatriz
author de la Rocha Muñoz, Andrés
author_facet de la Rocha Muñoz, Andrés
Melgarejo, Elena
Aragón, Carmen
López-Corcuera, Beatriz
author_role author
author2 Melgarejo, Elena
Aragón, Carmen
López-Corcuera, Beatriz
author2_role author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Fundación Ramón Areces
Banco Santander
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Transport
Glycine
Hyperekplexia Mutation
Chemical chaperone
Calnexin
topic Transport
Glycine
Hyperekplexia Mutation
Chemical chaperone
Calnexin
description Hyperekplexia is a rare sensorimotor syndrome characterized by pathological startle reflex in response to unexpected trivial stimuli for which there is no specific treatment. Neonates suffer from hypertonia and are at high risk of sudden death due to apnea episodes. Mutations in the human SLC6A5 gene encoding the neuronal glycine transporter GlyT2 may disrupt the inhibitory glycinergic neurotransmission and cause a presynaptic form of the disease. The phenotype of missense mutations giving rise to protein misfolding but maintaining residual activity could be rescued by facilitating folding or intracellular trafficking. In this report, we characterized the trafficking properties of two mutants associated with hyperekplexia (A277T and Y707C, rat numbering). Transporter molecules were partially retained in the endoplasmic reticulum showing increased interaction with the endoplasmic reticulum chaperone calnexin. One transporter variant had export difficulties and increased ubiquitination levels, suggestive of enhanced endoplasmic reticulum-associated degradation. However, the two mutant transporters were amenable to correction by calnexin overexpression. Within the search for compounds capable of rescuing mutant phenotypes, we found that the arachidonic acid derivative N-arachidonoyl glycine can rescue the trafficking defects of the two variants in heterologous cells and rat brain cortical neurons. N-arachidonoyl glycine improves the endoplasmic reticulum output by reducing the interaction transporter/calnexin, increasing membrane expression and improving transport activity in a comparable way as the well-established chemical chaperone 4-phenyl-butyrate. This work identifies N-arachidonoyl glycine as a promising compound with potential for hyperekplexia therapy.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/268706
url http://hdl.handle.net/10261/268706
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1016/j.neuropharm.2021.108543
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,228081

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