GBA D409V KI Mouse Model

GBA D409V KI mice have a knock-in of the D409V mutation in the murine GBA gene at exon 10, modelling the D409V mutation in the mature human GBA protein which causes Gaucher disease and is associated with late onset Parkinson‘s disease and Lewy body dementia.

The GBA gene is driven by the murine GBA promoter. Mice additionally contain loxP sites flanking exons 6 to 8 of the GBA gene, so it is possible to knockout this gene segment.

The most important characteristics of GBA D409V KI mice are:

• Increased soluble α-synuclein levels in the brain of GBA D409V KI^-/- mice
• Severely decreased GCase activity in the brain and liver of GBA D409V KI^+/- and GBA D409V KI^-/- mice from early on

Analysis of the GBA D409V KI mouse brain showed that a complete knock-in causes an increase of soluble but not insoluble murine α-synuclein levels (Figure 1A vs. B).

Figure 1: Murine α-synuclein levels in the brain of GBA D409V KI mice at the age of 12 months. A: Soluble murine α-synuclein levels, B: Insoluble murine α-synuclein levels. Mean + SEM; n = 12 per group. One-way ANOVA followed by Tukey’s post hoc test. *p<0.05.

Evaluation of GCase activity in the brain and liver of GBA D409V KI mice showed that the GBA-specific GCase activity in both tissues is already strongly decreased at the age of 4 months in GBA D409V KI^-/- as well as GBA D409V KI^+/- mice compared to wild type controls (Figure 2A and B). Homozygous knock-in (GBA D409V KI^-/-) resulted in a stronger effect that a hemizygous knock-in (GBA D409V KI^+/-).

Figure 2: GBA-specific (CBE-inhibitable) GCase activity in the brain and liver of GBA D409V KI mice. A: CBE-inhibitable GCase activity in the brain of 4 to 12 months old GBA D409V KI mice, B: CBE-inhibitable GCase activity in the liver of 4 to 12 months old GBA D409V KI mice. Mean + SEM; n = 12 per group. Two-way ANOVA followed by Dunett’s post hoc test. ***p<0.001.

Scantox offers a custom-tailored study design for the GBA D409V KI mouse model, and we are flexible to accommodate to your special interest.

We would be happy to test your compounds in the GBA D406V KI mouse model! The most common readouts are:

• GCase activity
• Substrate levels e.g. glucosylsphingosine
• Soluble α-synuclein levels

You might be also interested in these related topics:

• 4L/PS-NA transgenic mouse model
• CBE-induced Gaucher disease mouse model
• Pompe 6^neo mouse model

We are happy to receive your inquiry.