4L/PS-NA mice express low levels of prosaposin and saposins, as well as β-glucosidase (GCase) with a point mutation at position V394L/V394L and model Gaucher disease, the most common lysosomal storage disease (Sun et al., 2005). The neuronal disease variant is characterized by aggregated protein accumulations in the brain and associated neurological manifestations. Homozygous 4L/PS-NA mice thus present a strong enlargement of leukocytes and macrophages in visceral organs like spleen, thymus, lung and liver as early as 5 week of age. With increasing age, 4L/PS-NA mice develop motor deficits and reduced muscle strength that is accompanied by strong neuroinflammation in the cortex and hippocampus, and thus exhibiting the neuronopathic phenotype of Gaucher disease. Substrate measurements in brain homogenates showed significantly increased glucosylceramide and glucosylsphingosine levels as early as 5 week of age that further increase over age. Due to this strong phenotype, 4L/PS-NA mice have a reduced survival of up to 22 weeks.
Figure 1: Glucosylceramide accumulation and motor deficits of 5 to 18 week old 4L/PS-NA mice. A: GlcCer levels in the brain of 5, 12 and 18 week old 4L/PS-NA and control mice as well as C57Bl/6 mice, n = 5; B: Time animals spent hanging in the wire suspension test; n = 7. Mean + SEM. Two-way ANOVA with Bonferroni post hoc test. *p<0.05; **p<0.01. *differences between genotypes; #differences between age groups.
Figure 2: Neurofilament light chain (NF-L) levels in the plasma and CSF of 4L/PS-NA mice. NF-L levels in the plasma (A) and CSF (B) of 18 weeks old 4L/PS-NA mice as model of Gaucher disease; 4L/PS-NA: n = 7, 4L/PS+/+NA: n = 7, C57Bl/6: n = 7; One-way ANOVA with Tukey‘s multiple comparison test. Significance compared to 4L/PS+/+NA littermates and C57Bl/6 mice; Mean + SEM. ***p<0.001.
QPS Neuropharmacology offers a custom tailored study design for this model and we are flexible to accommodate to your special interest.. 4L/PS-NA mice show relevant features of Gaucher Disease already at young age. This allows for extraordinarily fast turn-around times.
We would be happy to test your compounds in the 4L/PS-NA mouse model! The most common readouts are:
- Enlarged leukocytes and macrophages in several visceral organs
- Muscle strength and motor deficits
- Glucocerebrosidate (GCase) activity measurement
- Substrate measurements of Glucosylceramide and Glucosylsphingosin
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QPS Neuropharmacology is also ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.