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

Marta Gómez-Grau,Carme Auladell,Josefina Casas,Lluïsa Vilageliu,Mara Dierssen,Júlia Albaigès,Daniel Grinberg

doi:10.1038/srep41931

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.

Highlights

Niemann-Pick disease type C (NPC; OMIM 257220) is a rare autosomal recessive, lysosomal and multisystemic neurodegenerative disorder caused by mutations in either the NPC1 or NPC2 gene
Our results showed that these novel NPC mouse models mimicked the main pathological features of human NPC, rendering them useful for testing new and approved therapeutic approaches
We describe the molecular and behavioural characterisation of new NPC mouse models bearing two mutations found in human patients

Summary

Introduction

Niemann-Pick disease type C (NPC; OMIM 257220) is a rare autosomal recessive, lysosomal and multisystemic neurodegenerative disorder caused by mutations in either the NPC1 or NPC2 gene. A metabolic and neurological phenotype mimicking human NPC disease has been described in Balb/C mice, which was the first mouse model of NPC and has been used for most of the NPC studies in mice. We generated two homozygous NPC mouse models bearing specific mutations: the Npc1imagine mouse carrying the deep intronic human mutation c.1554-1009. G >A, which we had previously observed in a Spanish NPC patient, and the Npc1pioneer mouse bearing the human mutation c.1920delG. Our results showed that these novel NPC mouse models mimicked the main pathological features of human NPC, rendering them useful for testing new and approved therapeutic approaches. The Npcimagine mouse, which, to the best of our knowledge, is the first NPC model bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC

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Results

Conclusion