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.
Highlights
Mutations in the leucine-rich repeat kinase 2 (LRRK2/PARK8) gene lead to the development of autosomal dominant Parkinson’s disease with pathology and characteristic motor and non-motor features highly similar to sporadic forms of the disease [1,2]
Three LRRK2 bacterial artificial chromosome (BAC) transgenic lines were generated on a Sprague–Dawley background: one expressing human wild-type LRRK2 and two mutant lines, expressing either the G2019S or R1441C mutant forms of the human gene
Understanding how LRRK2 mutations impact upon the function of dopaminergic neurons is important for elucidating the key pathophysiological changes underlying the core symptoms of Parkinson’s disease
Summary
Mutations in the leucine-rich repeat kinase 2 (LRRK2/PARK8) gene lead to the development of autosomal dominant Parkinson’s disease with pathology and characteristic motor and non-motor features highly similar to sporadic forms of the disease [1,2]. Parkinson’s disease-causing mutations lie in either the GTPase (R1441C/G/H), COR (Y1699C) or kinase (G2019S and I2020T) domains of the LRRK2 protein [4,5]. Transgenic rats expressing mutant LRRK2 have been developed [21,22,23] as rats are advantageous in allowing certain electrophysiological, behavioural and imaging techniques [24]. Together, these rodent models have provided important insight into the pathogenic effects of familial LRRK2, with most models exhibiting changes in some kind of locomotor activity and/or changes in striatal dopamine tone in the absence of progressive neurodegeneration of the substantia nigra pars compacta (SNc). Few exhibit age-dependent motor impairment that can be linked to altered dopaminergic neuron function or altered dopamine release, consistent with a Parkinsonian phenotype
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