1. LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.
- Author
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Sloan M, Alegre-Abarrategui J, Potgieter D, Kaufmann AK, Exley R, Deltheil T, Threlfell S, Connor-Robson N, Brimblecombe K, Wallings R, Cioroch M, Bannerman DM, Bolam JP, Magill PJ, Cragg SJ, Dodson PD, and Wade-Martins R
- Subjects
- Action Potentials, Aging pathology, Amino Acid Substitution, Animals, Cell Death genetics, Chromosomes, Artificial, Bacterial chemistry, Chromosomes, Artificial, Bacterial metabolism, Corpus Striatum drug effects, Corpus Striatum metabolism, Corpus Striatum pathology, Disease Models, Animal, Dopaminergic Neurons metabolism, Dopaminergic Neurons pathology, Female, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism, Male, Parkinson Disease drug therapy, Parkinson Disease metabolism, Parkinson Disease pathology, Promoter Regions, Genetic, Protein Domains, Rats, Rats, Transgenic, Substantia Nigra drug effects, Substantia Nigra metabolism, Substantia Nigra pathology, Aging metabolism, Antiparkinson Agents pharmacology, Dopaminergic Neurons drug effects, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Levodopa pharmacology, Mutation, Parkinson Disease genetics
- 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., (© The Author 2016. Published by Oxford University Press.)
- Published
- 2016
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