Characterization of new BAC LRRK2 WT and G2019S mouse models - Q&A with Dr. Zhenyu Yue

Dr. Zhenyu Yue of Mount Sinai School of Medicine discusses two new BAC Lrrk2 mouse models, recently published in Journal of Neuroscience.  As The Michael J. Fox Foundation partially funded this work, Dr. Kirsten Carlson of MJFF speaks with Dr. Yue about specific features of the models and their best use for studying PD.

Q: What is unique about the model and what need does it fulfill within the PD research community?

A:  We have used BAC (Bacterial artificial chromosome) transgenics, which is a much improved genetic approach for studying gene function under physiological conditions, to systematically characterize two lines of transgenic mice: LRRK2 wildtype overexpressor and PD-linked mutant G2019S, the single most common genetic cause of PD.  These two lines express similar expression patterns and levels of the two LRRK2 variants in the brains, providing us with a unique opportunity to predict the normal function of LRRK2 as well as role of LRRK2 G2019S in the pathogenesis of PD. We conclude that LRRK2 is involved in regulating striatal dopamine transmission and consequent control of motor function, whereas the G2019S mutation exerts pathogenic effects by impairing these functions of LRRK2 at initial stages of PD.

Another important feature of our models is the access to the enzymatic activity assay of brain LRRK2 proteins, which we believe have unique characteristics compared to that from other tissues or cell cultures. Previous in vitro studies have implicated hyperactive kinase activity of LRRK2 in neurotoxicity. Our initial study has found that, despite the enhanced kinase activity of brain LRRK2-G2019S protein (versus its Wt counterpart), the LRRK2-G2019S mice showed no sign of the neurodegeneration that is characteristic of PD. This offers support for the notion that the LRRK2-G2019S mutation can impair LRRK2 neuronal function without activating cell death pathways at early disease stages. Furthermore, this result has important implications for drug target validation of LRRK2, hinting that future testing of the hyperactive kinase hypothesis for the LRRK2 pathogenesis perhaps should look beyond cell death.

Q: How closely does the model mimic PD?

A: Our LRRK2-G2019S mice capture a key feature of PD, age-dependent striatal dopamine deficits. In addition, these mice have impaired striatal dopamine transmission, which is often found in pre-symptomatic PD patients through functional imaging studies. We have also found some non-motor function deficits in these mice and this part of work is still in progress.

Q: Are there pathological features present in the model that are not related to PD?

A:  So far we have not seen any abnormal phenotypes in LRRK2-G2019S mice that are unrelated to PD.

Q: What features of human PD are missing from the model?

A: Similar to previously reported LRRK2 models, our LRRK2 transgenic mice do not have the loss of midbrain dopamine neurons; LRRK2-G2019S mice do not develop obvious motor function abnormality. While this result suggests that these LRRK2-G2019S mice are hardly robust PD models, it does raise a question regarding the specific role of the G2019S mutation in the PD pathogenic process. In humans, the G2019S mutation has reduced penetrance; and therefore, other genetic factors or environmental effectors are likely to play important roles in altering LRRK2-G2019S mediated pathogenesis in PD.  Additional disease contributors (genetic and environmental) are apparently missing in these mice. 

Q: How is the model best used to study PD?

A:  These models will be best used to investigate initial pathogenic events in PD, such as striatal dopamine deficiency and potential effects of this deficiency in multiple neural pathways that precede and perhaps contribute to the later motor and non-motor symptoms. Thus these LRRK2 transgenics will be valuable models to reveal causative molecular events at initial stages of PD and to identify early biomarkers, diagnostics and therapeutic strategies.

For the research community, we expect that this unique pair of transgenic lines will be useful for studying upstream and downstream signaling of LRRK2 in vivo, tissue LRRK2 enzymatic activity, and “hot” questions such as the involvement of kinase/GTPase activity in disease onset, etc. We also believe that, in conjunction with a current major effort in studying a large number of G2019S carriers and patients (sponsored by MJFF), these mice will facilitate mechanistic understanding of the pathogenesis of PD.

Q: Replication and verification of the model's features will be important - is the model publicly available?

A: We are happy to share these LRRK2 models with the research community. We are currently working with our institute, Mount Sinai School of Medicine on an agreement to ship these mice to Jackson laboratory for broad distribution. They will be available following rederivation. We look forward to your comments, suggestions, and ideas!