UBC Theses and Dissertations
LRRK2 and the p.G2019S mutation in neuronal and systemic response to induced α-synuclein pathobiology MacIsaac, Sarah
Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which no disease-modifying treatments are currently available. PD is neuropathologically characterized by selective degeneration of nigral dopaminergic neurons and the presence of intraneuronal inclusions comprised primarily of α-synuclein (α-syn) in remaining cells. Mutations in several genes have been linked to PD, including those encoding α-syn and leucine-rich repeat kinase 2 (LRRK2). α-Syn pathology is present in the majority of patients with LRRK2 mutations, and a synergistic pathology has been proposed. A model of α-synucleinopathy was recently developed in which pathogenic α-syn pre-formed fibrils (PFFs) are used to seed aggregation of endogenous α-syn. To probe the role of LRRK2 and the influence of the p.G2019S mutation in induced α-syn pathology, differences in the response of wild-type (WT), LRRK2 knock-out (KO), and p.G2019S LRRK2 knock-in (KI) primary neuronal cultures to PFF treatment were examined. Further, behavioural consequences of intrastriatal PFF injection in WT and p.G2019S LRRK2 KI mice were compared. LRRK2 KO cultures appeared to be protected from PFF treatment, possibly due to a reduction in PFF uptake, more efficient degradation of pathogenic α-syn in neurites, and/or less neuron-to-neuron spread of pathogenic α-syn. Alternatively, p.G2019S LRRK2 KI cultures appeared to be more susceptible to PFF treatment, perhaps due to impaired handling of pathogenic α-syn by after fibril uptake. Behaviourally, WT and p.G2019S LRRK2 KI mice appear similarly vulnerable to motor deficits, but p.G2019S LRRK2 KI mice may be more susceptible to PFF-induced anxiety and cognitive deficits. Overall, this research points towards multiple roles for LRRK2 in α-syn pathogenic processes that may be altered by the p.G2019S mutation.
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