New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease

Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previousl...

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Autores: Gómez Grau, Marta, Albaigès, Júlia, Casas, Josefina, Auladell i Costa, M. Carme, Dierssen, Mara, Vilageliu i Arqués, Lluïsa, Grinberg Vaisman, Daniel Raúl
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/107267
Acceso en línea:https://hdl.handle.net/2445/107267
Access Level:acceso abierto
Palabra clave:Malalties de les glàndules endocrines
Lisosomes
Malalties rares
Endocrine diseases
Lysosomes
Rare diseases
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spelling New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the diseaseGómez Grau, MartaAlbaigès, JúliaCasas, JosefinaAuladell i Costa, M. CarmeDierssen, MaraVilageliu i Arqués, LluïsaGrinberg Vaisman, Daniel RaúlMalalties de les glàndules endocrinesLisosomesMalalties raresEndocrine diseasesLysosomesRare diseasesNiemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009G>A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compound heterozygosity with the c.1920delG mutation. Both the homozygotes for the c.1554- 1009G>A mutation and the compound heterozygotes recapitulated the hallmarks of NPC. Lipid analysis revealed accumulation of cholesterol in the liver and sphingolipids in the brain, with both types of transgenic mice displaying tremor and ataxia at 7-8 weeks of age. Behavioural tests showed motor impairment, hyperactivity, reduced anxiety-like behaviour and impaired learning and memory performances, features consistent with those reported previously in NPC animal models and human patients. These mutant mice, the first NPC models bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC.Nature Publishing Group2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/107267Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/srep41931Scientific Reports, 2017, vol. 7, num. 41931https://doi.org/10.1038/srep41931cc-by (c) Gómez et al., 2017http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1072672026-05-27T06:46:51Z
dc.title.none.fl_str_mv New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
title New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
spellingShingle New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
Gómez Grau, Marta
Malalties de les glàndules endocrines
Lisosomes
Malalties rares
Endocrine diseases
Lysosomes
Rare diseases
title_short New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
title_full New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
title_fullStr New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
title_full_unstemmed New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
title_sort New murine Niemann-Pick type C models bearing a pseudoexongenerating mutation recapitulate the main neurobehavioural and molecular features of the disease
dc.creator.none.fl_str_mv Gómez Grau, Marta
Albaigès, Júlia
Casas, Josefina
Auladell i Costa, M. Carme
Dierssen, Mara
Vilageliu i Arqués, Lluïsa
Grinberg Vaisman, Daniel Raúl
author Gómez Grau, Marta
author_facet Gómez Grau, Marta
Albaigès, Júlia
Casas, Josefina
Auladell i Costa, M. Carme
Dierssen, Mara
Vilageliu i Arqués, Lluïsa
Grinberg Vaisman, Daniel Raúl
author_role author
author2 Albaigès, Júlia
Casas, Josefina
Auladell i Costa, M. Carme
Dierssen, Mara
Vilageliu i Arqués, Lluïsa
Grinberg Vaisman, Daniel Raúl
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties de les glàndules endocrines
Lisosomes
Malalties rares
Endocrine diseases
Lysosomes
Rare diseases
topic Malalties de les glàndules endocrines
Lisosomes
Malalties rares
Endocrine diseases
Lysosomes
Rare diseases
description Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009G>A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compound heterozygosity with the c.1920delG mutation. Both the homozygotes for the c.1554- 1009G>A mutation and the compound heterozygotes recapitulated the hallmarks of NPC. Lipid analysis revealed accumulation of cholesterol in the liver and sphingolipids in the brain, with both types of transgenic mice displaying tremor and ataxia at 7-8 weeks of age. Behavioural tests showed motor impairment, hyperactivity, reduced anxiety-like behaviour and impaired learning and memory performances, features consistent with those reported previously in NPC animal models and human patients. These mutant mice, the first NPC models bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/107267
url https://hdl.handle.net/2445/107267
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/srep41931
Scientific Reports, 2017, vol. 7, num. 41931
https://doi.org/10.1038/srep41931
dc.rights.none.fl_str_mv cc-by (c) Gómez et al., 2017
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Gómez et al., 2017
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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