Matthew D Walker1, Mattia Volta2, Stefano Cataldi2, Katherine Dinelle3, Dayne Beccano-Kelly2, Lise Munsie2, Rick Kornelsen3, Chenoa Mah3, Patrick Chou2, Kimberley Co2, Jaskaran Khinda2, Marta Mroczek2, Sabrina Bergeron2, Katrina Yu2, Li Ping Cao2, Natalja Funk4, Thomas Ott5, Dagmar Galter6, Olaf Riess5, Saskia Biskup4, Austen J Milnerwood7, A Jon Stoessl8, Matthew J Farrer2, Vesna Sossi1. 1. Department of Physics & Astronomy, University of British Columbia, Vancouver, BC, Canada. 2. Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. 3. Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada. 4. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases DZNE, Tübingen, Germany. 5. Department of Medical Genetics, University of Tübingen, Tübingen, Germany. 6. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. 7. Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. 8. Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
Abstract
BACKGROUND: A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. OBJECTIVE: Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. METHODS: Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry. RESULTS: Transgenic rats had no abnormalities in measures of striatal dopamine function at 12 months. A behavioral phenotype was present, with LRRK2 p.G2019S rats performing significantly worse on the rotarod than non-transgenic littermates (26% reduction in average running duration at 6 months), but with normal performance in other motor tests. CONCLUSIONS: Neuroimaging using dopaminergic PET did not recapitulate prior studies in human LRRK2 mutation carriers. Consistently, LRRK2 p.G2019S rats do not develop overt neurodegeneration; however, they do exhibit behavioral abnormalities.
BACKGROUND: A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. OBJECTIVE: Assess the behavioral consequences of LRRK2p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from humanLRRK2 mutation carriers. METHODS:Rats overexpressing humanLRRK2p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry. RESULTS: Transgenic rats had no abnormalities in measures of striatal dopamine function at 12 months. A behavioral phenotype was present, with LRRK2p.G2019Srats performing significantly worse on the rotarod than non-transgenic littermates (26% reduction in average running duration at 6 months), but with normal performance in other motor tests. CONCLUSIONS: Neuroimaging using dopaminergic PET did not recapitulate prior studies in humanLRRK2 mutation carriers. Consistently, LRRK2p.G2019Srats do not develop overt neurodegeneration; however, they do exhibit behavioral abnormalities.
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