Publication in detail

Neurobiol Dis. 2015 Mar 31. pii: S0969-9961(15)00099-6. doi: 10.1016/j.nbd.2015.02.031.

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice.

Yue, M; Hinkle, K; Davies, P; Trushina, E; Fiesel, F; Christenson, T; Schroeder, A; Zhang, L; Bowles, E; Behrouz, B; Lincoln, S; Beevers, J; Milnerwood, A; Kurti, A; McLean, PJ; Fryer, JD; Springer, W; Dickson, D; Farrer, M; Melrose, H

Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; University of Dundee, DD1 4HN, Scotland, UK; Mayo Clinic College of Medicine and Mayo Clinic Rochester, Rochester, MN 55905, USA; Center for Applied Genetics, University of British Columbia, V6T 2B5, Canada.

Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate that the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

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