title: Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.
abstract: 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.
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yue
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Hinkle
authors.affiliation: MRC Phosphorylation Unit, University of Dundee, DD1 4HN, Scotland, UK.
authors.forename: P
authors.initials: P
authors.lastname: Davies
authors.affiliation: Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.
authors.forename: E
authors.initials: E
authors.lastname: Trushina
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Fiesel
authors.affiliation: Mayo Clinic Electron Microscopy Core Facility, Rochester, MN 55905, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Christenson
authors.affiliation: Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Schroeder
authors.affiliation: Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bowles
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: B
authors.initials: B
authors.lastname: Behrouz
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lincoln
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Beevers
authors.affiliation: Center for Applied Neurogenetics, University of British Columbia, V6T 2B5, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Milnerwood
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kurti
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: McLean
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: W
authors.initials: W
authors.lastname: Springer
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Center for Applied Neurogenetics, University of British Columbia, V6T 2B5, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Farrer
authors.affiliation: Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. Electronic address: melrose.heather@mayo.edu.
authors.forename: H L
authors.initials: HL
authors.lastname: Melrose
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009043:Motor Activity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D045442:Rotarod Performance Test; D016875:tau Proteins / Q000378:metabolism
chemical_list: C558298:Mapt protein, mouse; D016875:tau Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
keywords: Dopamine; Gene-targeted mouse model; Microdialysis; Mitochondria; Parkinson's disease
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