The LRRK2 G2019S gain-of-function mutation is frequently observed in Parkinson’s disease patients. Selective LRRK2 inhibitors have thus been proposed as promising compounds for the treatment of PD.
At QPS Neuropharmacology, two rodent models are now available to test your LRRK2 inhibitors. LRRK2-G2019S Knock-In mice expressing murine LRRK2 with G2019S mutation and human LRRK2 G2019S transgenic rats overexpressing human LRRK2 with G2019S mutation next to the rat’s wild type LRRK2. Both models display only mild age-specific motor abnormalities and similar cognitive function compared to non-transgenic control animals, up to an age of 12 months.
Evaluation of total and phosphorylated LRRK2 in the brain of 10 weeks old LRRK2 G2019S mice and non-transgenic mice showed no differences in total LRRK2 (Fig.1A) and LRRK2-pS935 levels (Fig.1B), while LRRK2-pS1292 levels were significantly increased in LRRK2 G2019S mice (Fig.1C). In contrast, 10 weeks old human LRRK2 G0219S transgenic rats displayed approximately 10-fold increased brain levels of total LRRK2 (Fig. 1D) and significantly higher LRRK2-pS935 levels (Fig. 1E), whereas LRRK2-pS1292 levels were not significantly changed compared to non-transgenic littermates (Fig. 1F). The differential LRRK2 phosphorylation pattern in the transgenic rat model is likely due to the strong overexpression of the human mutant protein, whereas LRRK2 G2019S mice carry the gain-of-function mutation within the endogenous murine Lrrk2 gene.
Figure 1. Total and phospho-LRRK2 levels in LRRK2 G2019S Knock-In mice and human LRRK2 G2019S transgenic rats. LRRK2 G2019S Knock-In mice and human LRRK2 G2019S rats were evaluated for total (t)LRRK2 (A, D), LRRK2-pS935 (B, E), and LRRK2-pS1292 (C, F) levels using a Mesoscale Discovery (MSD) immunosorbent assay. Mean ± SEM; n=8 per group (mice) and n=3-4 per group (rats), unpaired t-test. **p<0.01, ***p<0.001, ns, not significant.
Both LRRK2 G2019S mice and human LRRK2 G2019S transgenic rats are therefore suitable models to assess the efficacy of LRRK2 inhibitors on LRRK2 kinase activity in vivo. In such studies, MLi-2 could be used as reference compound.
Contact us today to discuss your in vivo study in the LRRK2-G2019S animal models!