Research Models

HGBA L444P Tg on Gba1 KO Mouse

Synonyms: HGBA L444P/Gba−/−, Tg human GCaseL444P

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Species: Mouse
Genes: GBA1, Gba1
Modification: GBA1: Transgenic; Gba1: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: Gba1tm1.1Clk Tg(CAG-GBA*L483P)8Clk/Mmjax
Genetic Background: Mixed C57BL/6, 129 Sv background.
Availability: Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 050598-JAX, Cryopreserved.

Modification Details:

The HGBA L444P/Gba−/− mouse carries a mutated human L444P HGBA transgene on a mouse Gba1 null (Gba−/−) background (Sanders et al., 2013). The mating scheme to achieve this genetic combination is to cross a haplodeficient Gba−/+ parent to a second Gba−/+ parent that additionally carries one copy of the HGBA L444P transgene.

Summary
This mouse model carries one copy of a human HGBA L444P transgene, which encodes a mutated acid β-glucosidase (also known as β-glucocerebrosidase or GCase), on a mouse Gba1 null background and is referred to as the HGBA L444P/Gba−/− mouse (Sanders et al., 2013). This hemizygous expression of a mutated human transgene rescues homozygous Gba1 null mice from perinatal lethality.

Overall Health
HGBA L444P Gba−/− mice are fertile and have a normal lifespan (Sanders et al., 2013). No obvious skin phenotype was observed in neonatal HGBA L444P/Gba−/− mice.

GCase activity in the spleen, liver, and cerebrum was lower than that observed in transgene-negative Gba+/+ control mice (Sanders et al., 2013). HGBA L444P/Gba−/− mice also show progressive and early elevations in glucosylceramide in the spleen and liver, but not in the cerebrum or cerebellum, as well as progressive elevations in glucosylsphingosine in all three tissues. Furthermore, Gaucher cells were observed starting at 45 weeks of age in the spleen but not in the liver, lung, or bone marrow up to 70 weeks of age.

Overall health seemed intact based on the absence of evidence of splenomegaly, hepatomegaly, and hematologic disturbances in HGBA L444P/Gba−/− mice, even at older ages. No obvious evidence of neurological dysfunction and no obvious motor, behavioral, or cognitive features were noted (Sanders et al., 2013; personal communication, Lorne Clarke, July 2024).

Neural Health
No evidence of neuropathology or of α-synuclein or ubiquitin deposition was observed in older HGBA L444P Gba−/− mice (Sanders et al., 2013).

Related Strains
The HGBA N370S/Gba−/− mouse line was generated concurrently (Sanders et al., 2013) and is described in more detail in its respective model page.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • α-synuclein Inclusions
  • Motor Impairment
  • Neuronal Loss

No Data

  • Dopamine Deficiency
  • Non-Motor Impairment
  • Neuroinflammation
  • Mitochondrial Abnormalities

Neuronal Loss

Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.

α-synuclein Inclusions

Older HGBA L444P /Gba−/− mice do not show evidence of α-synuclein inclusions.

Motor Impairment

No obvious phenotypic features noted.

Q&A with Model Creator

Expert/Creator Q & A with Lorne Clarke

What would you say are the unique advantages of this model? 
The unique advantage of this model is the fact that these mice only express human mutant Gba. Therefore, this mouse line can effectively be used to study biomarkers related to Gba deficiency caused by the most common Gba alleles. In addition, this mouse strain can be used to generate stem cells from any tissue and subsequently be used to study the effects of the common Gba alleles on metabolic pathways.

What do you think this model is best used for?
The utility is basically limitless and based on the desire of an investigator to study human mutant Gba expression. This can be used to evaluate therapeutics that aim to target stabilizing human mutant Gba proteins in a true in vivo system.

What caveats are associated with this model?
The only caveat is that the mouse strain produces only human Gba and expresses it at a fairly high level, thus the high expression may not be reflective of true in vivo levels of Gba expression.

Anything else useful or particular about this model you think our readers would like to know?
The mouse is very stable with no obvious detrimental effects.

Last Updated: 28 Aug 2024

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References

Research Models Citations

  1. HGBA N370S Tg on Gba1 KO Mouse

Paper Citations

  1. Sanders A, Hemmelgarn H, Melrose HL, Hein L, Fuller M, Clarke LA. Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease. Blood Cells Mol Dis. 2013 Aug;51(2):109-15. Epub 2013 Apr 30 PubMed.

External Citations

  1. Mutant Mouse Regional Resource Centres (MMRRC), Stock# 050598-JAX

Further Reading

No Available Further Reading