Species: Mouse
Genes: Gba1
Modification: Gba1: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: B6.129X1(C)-Gba1^tm1.1Eginn/J
Genetic Background: Mixed C57BL/6NCr and C57BL/6NJ background
Availability: Available through The Jackson Laboratory, Stock# 024574, Cryopreserved.

Modification Details:

L444P KI mice were generated using a loxP replacement vector, resulting in the insertion of a point mutation of leucine to proline (L444P) in exon 10 of the Gba1 gene (Ginns et al., 2014).

Summary
These Gba1 knock-in (KI) mice carry a leucine to proline mutation (L444P) in exon 10 of the mouse Gba1 (glucosidase [GCase], beta, acid 1) gene, resulting in Gba deficiency (Ginns et al., 2014; The Jackson Laboratory). This mutation is commonly found in humans with Gaucher disease, and people with GBA1 mutations have a higher risk of developing Parkinson’s disease.

Homozygous L444P KI mice are viable and fertile. Compared to wild-type mice, the GBA enzyme (GCase) activity of KI mice is reduced to 21 percent in liver, 32 percent in spleen, and 35 percent in brain (Ginns et al., 2014). Glucosylsphingosine, but not glucosylceramide, accumulation was detected—though not significantly—in the brain and liver (Furderer et al., 2024). In mice carrying one KI L444P allele on a Gba1 null background, the lipid accumulation was more severe and significant in the brain. L444P KI mice also have significantly reduced levels of glycosylated GCase in brain lysates, but total levels of GCase are unchanged from that seen in samples from wild-type mice.

In the original model report, lipid-laden Gaucher cells, as characterized by abnormal lysosomal storage, were observed in the liver of KI mice (Ginns et al., 2014). However, in a more recent study, neither 6- nor 14-month-old KI mice displayed Gaucher cells in the liver or spleen (Furderer et al., 2024). The discrepant findings between these two published papers could be due to genetic background as the colonies were kept independently for over 20 years (Ellen Sidransky, personal communication).

Neuropathology
In L444P KI mice aged about 1 year, increases in α-synuclein deposition and astroglial activation (as detected by GFAP immunoreactivity) were observed in the striatum compared to wild-type controls (Ginns et al., 2014). However, in another study, no differences compared to wild-type mice were observed in GFAP or Iba-1 (microglia marker) staining in the striatum of 14-month-old KI mice (Furderer et al., 2024). Moreover, cellular morphology of the GFAP or Iba-1 stained cells also did not differ. In this more recent study, levels of α-synuclein in brain extracts from 6- and 14-month-old KI mice also did not significantly differ from wild-type controls. As noted above, the differences between the two studies could be due to genetic background as the colonies were kept independently for over 20 years (Ellen Sidransky, personal communication).

Tyrosine hydroxylase immunostaining was used to assess dopaminergic cell numbers in the substantia nigra, and no differences were observed between L444P KI and wild-type mice at 14 months of age (Furderer et al., 2024). 

Motor Function
In 16-month-old L444P KI mice compared to wild-type controls, no differences were detected in balance, as measured by Rotarod and balance beam tests (Furderer et al., 2024).

Phenotype Characterization

Q&A with Model Creator

Q&A with Ellen Sidransky

What would you say are the unique advantages of this model?

The mouse model carries the Gba1 Leu444Pro point mutation, which is probably the most frequent GBA1 pathogenic variant world-wide. The mouse model shows substantial GCase activity loss, which is seen in human patients carrying the same mutation as well. However, there is very little clinical phenotype.

What do you think this model is best used for?

The mouse model can be used to test in vivo efficacy of some therapies, such as small molecule drugs and enzyme replacement, by monitoring  GCase activity and GlcSph levels.

What caveats are associated with this model?

While the mouse model shows substantial reduction of GCase activity and substrate accumulation, it does not consistently recapitulate the neuropathology phenotype associated with PD. Thus, the mouse model can’t be solely used as a mouse model of PD for pathology research or preclinical study purposes. It also does not exhibit much organomegaly or Gaucher cells, typical of human Gaucher disease.

Anything else useful or particular about this model you think our readers would like to know?

Because neuropathological findings of the mouse model are discrepant between two previous studies (Ginns et al., 2014 and Furderer et al., 2024), additional phenotype evaluations may be necessary using larger samples size for quantitative analysis.

Mating with the null allele mouse results in a mouse with lower enzymatic activity, but still few Gaucher manifestations.

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References

Paper Citations

1. Ginns EI, Mak SK, Ko N, Karlgren J, Akbarian S, Chou VP, Guo Y, Lim A, Samuelsson S, LaMarca ML, Vazquez-DeRose J, Manning-Boğ AB. Neuroinflammation and α-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction. Mol Genet Metab. 2014 Feb;111(2):152-62. Epub 2013 Dec 11 PubMed.

External Citations

1. The Jackson Laboratory
2. The Jackson Laboratory, Stock# 024574

Further Reading