Article type: Research Article
Authors: Walker, Matthew D. | Volta, Mattia | Cataldi, Stefano | Dinelle, Katherine | Beccano-Kelly, Dayne | Munsie, Lise | Kornelsen, Rick | Mah, Chenoa | Chou, Patrick | Co, Kimberley | Khinda, Jaskaran | Mroczek, Marta | Bergeron, Sabrina | Yu, Katrina | Cao, Li Ping | Funk, Natalja | Ott, Thomas | Galter, Dagmar | Riess, Olaf | Biskup, Saskia | Milnerwood, Austen J.; | Stoessl, A. Jon; | Farrer, Matthew J. | Sossi, Vesna
Affiliations: Department of Physics & Astronomy, University of British Columbia, Vancouver, BC, Canada | Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada | 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 | Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases DZNE, Tübingen, Germany | Department of Medical Genetics, University of Tübingen, Tübingen, Germany | Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Note: [] These authors contributed equally to this work. Correspondence to: Matthew D. Walker, University of British Columbia, Pacific Parkinson's Research Centre, M36 Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. Tel.: +1 604 822 7149; Fax: +1 604 822 7866; E-mail: mwalker@physics.ubc.ca
Note: [] These authors contributed equally to this work.
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.
Keywords: Parkinson's disease, LRRK2 protein, human, dopaminergic neurons, transgenic rats, dopamine, brain imaging, positron-emission tomography
DOI: 10.3233/JPD-140344
Journal: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 483-498, 2014
