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Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s Disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neuro-transmission, membrane and cytoskeletal dynamics and protein degradation. We have created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of this line up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis. Our results show that the dopaminergic system is essentially intact in LRRK2 knockout mice, although measurements of in vivo extracellular release revealed a trend towards delayed KCl-evoked dopamine release. In the open field, LRRK2 knockout mice display anxiety like phenotypes, indicating that the limbic system may be impacted by loss of LRRK2. Surprisingly, aged heterozygous and homozygous knockout mice out-performed their wild type littermates during rotarod testing, indicating cerebellar sensory changes and perhaps suggesting that lower levels of LRRK2 have some beneficial effects during aging. Finally, we confirm that loss of LRRK2 causes degeneration in the kidney, which was accompanied by a compensatory increase in autophagy. These findings may be an important consideration for future anti-LRRK2 therapies.



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