1. Sporadic Parkinson disease (PD) involves a complex interaction of three major risk factors: genetic susceptibility, environmental toxicity, and ageing. We developed a new experimental protocol using a mouse model that carries a specific mutation at the same genetic location in parallel with the humans. We administered twice weekly oral doses of a naturally occurring pesticide (rotenone) over half the lifespan of the mouse to mimic chronic exposure to environmental toxicity. Ageing is inherent in the course of experiments. We found brain abnormalities and locomotor deficits in the new model are more faithful of the human PD than other existing models.
2. Although our LRRK2 knockin mice do not show obvious disease phenotype, they had greater reduction in striatal dopamine uptake, with locomotor deficits that were slower to recover than wild-type mice after reserpine injection (dopaminergic vesicle uptake blocker). These indicate that the mutant mice are more susceptible to striatal synaptic dysfunction even at young age, supporting its relevance in PD.
3. We cross-bred a new colony of mutant LRRK2 mice with fluorescent dopaminergic cells. This enables us to study, isolate, or image live dopaminergic neurons that degenerate in PD with greater ease and clarity. Our gene profiling studies showed significant differences in expression of several genes in nigrostriatal dopaminergic neurons of aged mutant mice.
4. The role of LRRK2 in phosphorylation of Rab GTPases proteins was explored using our LRRK2 mutant mice, including live mouse embryonic fibroblasts. This has important implications for the development of new treatments for PD such as LRRK2 inhibitors.
5. There is a lack of treatment modalities that can modify the progression of PD. Existing treatments relieve symptoms without altering its progression. It is still unclear how PD develops and progresses. Our model can help elucidate its complex disease processes and test therapeutic agents on these processes.