First published Lrrk2 mutation mouse model of PD: Q&A with Dr. Chenjian Li

A discussion of the new BAC Lrrk2 mouse model developed by Dr. Chenjian Li and colleagues, published today in Nature Neuroscience.  Dr. Kirsten Carlson of The Michael J. Fox Foundation, which partially funded this work, asks Dr. Li about the model's features and limitations and his hopes for its widespread use by the PD research community.  More information on this strain may be found in the Jax Mice Database.

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

CL: It’s the first reported mouse model for LRRK2 mutations, and it recapitulates some key PD-like phenotypes.  An interesting feature of this mouse is its age-dependent and progressive movement deficit which is L-dopa responsive.  Additionally, the construct makes use of a bacterial artificial chromosome (BAC) which covers the whole human LRRK2 gene. 

The PD research community always needs a variety of models.  Take alpha-synuclein for example: although there have been many very interesting models, each useful in its own way, researchers are still generating new ones (fragment models, specific promoter-driven ones, etc). Our LRRK2 model compliments this list of PD models, and it offers some novel features.  It is worth mentioning that our mice and BAC clones are not the end of PD model building efforts, instead, they are the beginning of further work.  Together with our collaborators, we have already started using these validated BACs to engineer other human disease related mutations, as well as other manipulations for testing specific hypotheses genetically.  For example, we are currently engineering GTPase dead and kinase dead mutations on top of the R1441G mutation to address whether the GTPase or kinase domains of LRRK2 are required for LRRK2-mediated pathogenesis. 

KC: How does your model mimic human PD?

CL: It recapitulates the progressive reduction of movement at the behavioral level, dopamine release deficit at the circuitry level, and DA neuron atrophy and neurite degeneration at the histopathological level. Hyperphosphorylation of tau is another feature we observed.  Although tauopathy is only a minor aspect of idiopathic PD, it is worth pointing out that some LRRK2 patients did have tauopathy in the absence of Lewy body pathology.

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

CL: So far we haven’t found any.  All of the phenotypes we observed to date are related to human PD. However, we have only had time to look at the “cardinal” PD phenotypes, and therefore naturally that’s what we see.  It is possible that later, something new will come up. However, if that happens, we shouldn’t just discard those observations as irrelevant; instead, we should go back to human patients and ask if those pathological features are present but overlooked before. 

KC: What features of human PD are missing from your model?

CL: Overt and robust DA neuronal death.  Although there is statistically significant DA cell body atrophy and a striking DA neurite degeneration, cell death is not yet significant at the age of 10 months. It will be important to examine for this at a later time point.

Another missing feature is robust Lewy body pathology.  This might be due to the fact that there is no human alpha-synuclein in these mice.  Mice have endogenous alpha-synuclein which is not prone to aggregation.  We are currently examining whether there are micro-aggregates, which has been suggested as a possible toxic species.

KC: How would your model be best used to study PD?

CL: Probably the best usage is simply to let people use it in whichever experiment they feel compelled to pursue. I believe that fellow scientists in academia or industry are very intelligent and creative, and each has some great ideas to test---be it mechanistic studies or drug testing. Of course, we also have directions that we are passionate to pursue, such as investigating LRRK2 kinase substrates and signaling pathways, axonal and dendritic degeneration, and some drug testing including small molecules or RNAi approaches, DA neurons induced from stem cells for replacement therapy, etc.

KC: Replication and verification of these features will be important - is the model publicly available?

CL: Absolutely.  Not only for replication and verification, but most importantly to test new hypotheses.

We made these mice for us and for fellow scientists in the field.  Weill Cornell Medical College has standard MTAs for academic labs and contracts for industry; the model is currently being re-derived at Jackson Laboratories and will be made available to the research community as soon as it is ready.

We hope that by providing this unique model to others, we can facilitate the development of new ideas.  Additionally, we’re happy to combine efforts through collaboration for potentially maximum impact.