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

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  • dc.contributor.author Gómez Grau, Martaca
  • dc.contributor.author Albaigès-Ràfols, Júliaca
  • dc.contributor.author Casas, Josefinaca
  • dc.contributor.author Auladell, Carmeca
  • dc.contributor.author Dierssen, Maraca
  • dc.contributor.author Vilageliu, Lluïsaca
  • dc.contributor.author Grinberg, Danielca
  • dc.date.accessioned 2018-07-23T07:58:32Z
  • dc.date.available 2018-07-23T07:58:32Z
  • dc.date.issued 2017
  • dc.description.abstract 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.1554-1009 G > 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.1554-1009 G > 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.
  • dc.description.sponsorship This study was partly funded by grants from the Spanish Ministry of Science and Innovation (SAF2011-25431, SAF2013-49129-C2-1-R and SAF2014-56562-R) and from the Catalan Government (2014SGR/932 and SGR2014/1125), as well as the Addi and Cassi Fund. We are particularly grateful for the support from the Addi and Cassi Fund, who also provided the heterozygous mice. The Centre for Genomic Regulation has received support as a Severo Ochoa Centre of Excellence SEV- 2012-0208. We thank Alexandre Garcia for technical assistance. The authors are also grateful for the support from the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), which is an initiative of the ISCIII. MGG was supported by a grant from the University of Barcelona (APIF).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Gómez-Grau M, Albaigès J, Casas J, Auladell C, Dierssen M, Vilageliu L et al. New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease. Sci Rep. 2017 Feb 7;7:41931. DOI: 10.1038/srep41931
  • dc.identifier.doi http://dx.doi.org/10.1038/srep41931
  • dc.identifier.issn 2045-2322
  • dc.identifier.uri http://hdl.handle.net/10230/35223
  • dc.language.iso eng
  • dc.publisher Nature Publishing Groupca
  • dc.relation.ispartof Scientific Reports. 2017 Feb 7;7:41931
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-25431
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49129-C2-1-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-56562-R
  • dc.rights © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Metabolic disorders
  • dc.subject.keyword Niemann-Pick disease type C
  • dc.subject.keyword Anxiety disorders
  • dc.title New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the diseaseca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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