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Enzyme and substrate measurements in the Gaucher disease mouse model 4L/PS-NA

QPS Neuropharmacology

QPS Austria is now able to offer Glucocerebrosidase (Gcase) activity as well as Glucosylceramide (GlcCer) and Glucosylsphingosine (GlcSph) measurements in your 4L/PS-NA study animals! These animals express the homozygous GbaV394L/V394L mutation (4L), have a complete prosaposin knockout (PS-) and a homozygous prosaposin transgene (NA) resulting in hypomorphic prosaposin levels.

Measurement of GCase activity in brain tissue of 5, 12 and 18 weeks old 4L/PS-NA and 4L/PS+/+NA control animals with the 4-MUG assay shows that GCase activity in both genotypes is reduced to only about 6% compared to C57Bl/6 animals (Fig.1). For intervention studies targeting the GCase activity we thus suggest to use C57Bl/6 mice as control group, since 4L/PS+/+NA littermates present a similar reduction in the GCase activity compared to 4L/PS-NA Gaucher disease animals.

glucocerebrosidase Figure 1. Relative GCase activity in 4L/PS-/+NA and 4L/PS-NA cortical tissue compared to C57Bl/6 mice measured with 4-MUG assay (n=6 per group). Statistical analysis using Two-way ANOVA followed by Bonferroni’s post hoc test; Mean+SEM.

Measurement of substrates GlcCer and GlcSph was performed by ultra high performance liquid chromatography coupled to tandem mass spectrometry by our partner Pronexus Analytical AB. Brain tissue of 5, 12 and 18 weeks old 4L/PS-NA, 4L/PS+/+NA control animals and 12 weeks old C57Bl/6 animals was analyzed resulting in a progressive increase of GlcCer and GlcSph levels in 4L/PS-NA mice but only a minor increase in 4L/PS+/+NA mice. C57Bl/6 mice presented no substrate levels at the age of 12 weeks (Fig.2A, B). These results suggest that 4L/PS+/+NA as well as C57Bl/6 mice are valuable control animals for substrate measurements in your 4L/PS-NA study.

glucosylceramide
glucosylsphingosine

Figure 2. Quantification of cerebral Glucosylceramide and Glucosylsphingosine in 5 to 18 weeks old 4L/PS-NA mice. A: Glucosylceramide in µg/g wet weight. B: Glucosylsphingosine in ng/g wet weight. A and B: 12 weeks old C57Bl/6 mice were added as additional control group but this group was excluded from statistical analysis. Mean + SEM; n = 5; *differences between genotypes; # differences between age groups; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.


Meet us at the 2nd International Congress on Advanced Treatments in Rare Diseases 2019 in Vienna

The clinical and neuropharmacology team of QPS Austria will attend the RARE 2019 congress and are pleased to meet you at our booth.

Join us from March 4-5 in Vienna, Austria at the HILTON VIENNA, Am Stadtpark 1, Vienna

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