A novel mouse model of Niemann–Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations

Abstract

We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.

Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C

“…Homozygous mutants of both strains (Npc1 Ϫ/Ϫ ) along with wild type littermates (Npc1 ϩ/ϩ ) were generated by crossing heterozygous mutant (Npc1 ϩ/Ϫ ) males and females in house. Npc1 nih mouse pups were genotyped according to published protocols (8), and Npc1 nmf164 mice were genotyped based on PCR followed by digestion with BstEII (29). In this study, unless otherwise indicated, Npc1 nih mice were used.…”

“…We further examined plasma from Npc1 nmf mouse. Previous studies suggested that Npc1 nmf mice in the C57BL/6J background have a life span of ϳ112 days and develop progressive disease (29). BALB/c Npc1 nmf have a comparable life span (ϳ120 -125 days) and exhibited weight loss from 85 to 90 days (19).…”

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…These mice are asymptomatic at birth but develop ataxia and die within ‫ف‬ 3 months. A more recent mouse model carries the D1005G mutation in NPC1 ( 73 ). This mutation is in the cysteinerich loop of NPC1, the site at which the most common mutations occur in human NPC patients, and these mice have a more slowly progressing disease than that of NPC1-null by guest, on May 10, 2018 www.jlr.org Downloaded from addition, the formation of presynaptic SNARE complexes, the interaction between synaptobrevin and synaptophysin, the fusion of synaptic vesicles with presynaptic membranes, and the sorting of synaptic vesicles during endocytosis all depend on cholesterol (120)(121)(122)(123)(124).…”

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

“…Recently, a mouse model with a point mutation in NPC1 (D1005G) has been described [94], and mouse models with other mutations are being developed. These mouse models will provide the capability of testing HDACi therapy in mouse models.…”