UBC Theses and Dissertations
The nigrostriatal dopamine system in the leucine-rich repeat kinase 2 G2019S knock-in mouse model of Parkinson's disease Paschall, Sarah Afton
Mutations on the leucine-rich repeat kinase 2 (LRRK2) gene are the most common variants responsible for idiopathic Parkinson’s disease (PD). Historically, PD is thought of as a late-stage neurodegenerative disease resulting from the loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy pathology. Current treatments focus on the dopaminergic aspect of this disease, without addressing or successfully halting the underlying causes of this disease. The LRRK2 G2019S mutation is the single most common genetic risk factor for Parkinson’s disease and leads to increased kinase activity with subtle effects on the timing of nigrostriatal dopaminergic transmission. Here, using a genetically faithful G2019S knock-in (GKI) mouse model at multiple age points, although no differences were seen in monoamine, glutamate, or GABA release by in vivo microdialysis of the dorsolateral striatum, more temporally sensitive investigation revealed subtle release augmentation in mutants. Using fast-scan cyclic voltammetry to examine dopamine release and reuptake on a millisecond timescale in acute striatal slices at early (<3 months) and later age points (~12 months), alterations in dopamine release were observed with repeated stimulation and increased decay constant in mutants. In GKI mice dopamine release is augmented and responds differently across age points to pharmacological D2 receptor agonism and dopamine transporter (DAT) inhibition. LRRK2 is thought to be involved in synaptic vesicle storage and recycling and GKI mutation in mice leads to augmented dopamine release from an early age that is not attenuated by DAT inhibition, indicating other mechanisms (e.g. altered release / vesicle cycling) are affected and play a role in this alteration from early stages (<3 months, potentially earlier) in response to this mutation. Elucidation of the function of LRRK2 and the deleterious effects caused by the G2019S mutation will help target neuroprotective therapies to delay or halt disease progression.
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