title: Behavioral deficits and striatal DA signaling in LRRK2 p.G2019S transgenic rats: a multimodal investigation including PET neuroimaging.
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.
authors.affiliation: Department of Physics & Astronomy, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Walker
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mattia
authors.initials: M
authors.lastname: Volta
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cataldi
authors.affiliation: Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Dinelle
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dayne
authors.initials: D
authors.lastname: Beccano-Kelly
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lise
authors.initials: L
authors.lastname: Munsie
authors.affiliation: Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Rick
authors.initials: R
authors.lastname: Kornelsen
authors.affiliation: Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Chenoa
authors.initials: C
authors.lastname: Mah
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chou
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Co
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jaskaran
authors.initials: J
authors.lastname: Khinda
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Marta
authors.initials: M
authors.lastname: Mroczek
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bergeron
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Katrina
authors.initials: K
authors.lastname: Yu
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Cao
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases DZNE, Tübingen, Germany.
authors.forename: Natalja
authors.initials: N
authors.lastname: Funk
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ott
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases DZNE, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: 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.
authors.forename: Austen J
authors.initials: AJ
authors.lastname: Milnerwood
authors.affiliation: 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.
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.affiliation: Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.affiliation: Department of Physics & Astronomy, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D009043:Motor Activity / Q000235:genetics*; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics*; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D045442:Rotarod Performance Test; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D017448:Receptors, Dopamine D2; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
keywords: LRRK2 protein; Parkinson's disease; brain imaging; dopamine; dopaminergic neurons; human; positron-emission tomography; transgenic rats