title: LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18-21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics.
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Max
authors.initials: M
authors.lastname: Sloan
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Javier
authors.initials: J
authors.lastname: Alegre-Abarrategui
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Dawid
authors.initials: D
authors.lastname: Potgieter
authors.affiliation: Oxford Parkinson's Disease Centre, Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology and.
authors.forename: Anna-Kristin
authors.initials: AK
authors.lastname: Kaufmann
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Richard
authors.initials: R
authors.lastname: Exley
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Thierry
authors.initials: T
authors.lastname: Deltheil
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Sarah
authors.initials: S
authors.lastname: Threlfell
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Natalie
authors.initials: N
authors.lastname: Connor-Robson
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Katherine
authors.initials: K
authors.lastname: Brimblecombe
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wallings
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics.
authors.forename: Milena
authors.initials: M
authors.lastname: Cioroch
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Oxford Parkinson's Disease Centre, Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology and.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Bolam
authors.affiliation: Oxford Parkinson's Disease Centre, Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Magill
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, stephanie.cragg@dpag.ox.ac.uk paul.dodson@pharm.ox.ac.uk richard.wade-martins@dpag.ox.ac.uk.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
authors.affiliation: Oxford Parkinson's Disease Centre, Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology and stephanie.cragg@dpag.ox.ac.uk paul.dodson@pharm.ox.ac.uk richard.wade-martins@dpag.ox.ac.uk.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Dodson
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, stephanie.cragg@dpag.ox.ac.uk paul.dodson@pharm.ox.ac.uk richard.wade-martins@dpag.ox.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
mesh_terms: D000200:Action Potentials; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D016923:Cell Death / Q000235:genetics; D022202:Chromosomes, Artificial, Bacterial / Q000737:chemistry / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics* / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D000072417:Protein Domains; D051381:Rats; D055647:Rats, Transgenic; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2