Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 (KI) 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 KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line 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.

Original publication

DOI

10.1016/j.nbd.2015.02.031

Type

Journal article

Journal

Neurobiol Dis

Publication Date

06/2015

Volume

78

Pages

172 - 195

Keywords

Dopamine, Gene-targeted mouse model, Microdialysis, Mitochondria, Parkinson's disease, Animals, Autophagy, Brain, Dopamine, Dopaminergic Neurons, Female, Gene Knock-In Techniques, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Motor Activity, Protein-Serine-Threonine Kinases, Rotarod Performance Test, tau Proteins