Lei, Si Hang; (2023) Brain regions and cell type specific Wnt signalling changes in Parkinson’s disease mouse models. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parkinson’s disease (PD) is a late onset neurodegenerative disease characterised by the loss of dopaminergic neurons with motor and cognitive symptoms. Different mutations have been identified as a risk factor or direct cause of the disease. LRRK2 gene mutation is a major cause of sporadic and inherited Parkinson’s disease (PD), but the exact mechanism of how LRRK2 mutation causes PD remains to be revealed. LRRK2 is a huge complex protein with both GTPase and Kinase domains. G2019S is the most common LRRK2 mutation on the kinase domain. There is accumulate evidence showing LRRK2 as a scaffolding protein interacts with canonical and noncanonical Wnt signalling pathways. These pathways play an important role on immune responses, nerves system development as well as neuronal maintenance./ This project aims to study how LRRK2 influence Wnt signalling pathways activities, we used LRRK2 wild type (WT), LRRK2 knock-out (KO) and G2019S knock-in (KI) mouse models in the project. We identified the brain regions with Wnt and NFAT signalling activities by applying biosensor system via lentiviral construct transduction into the brain at P0 and investigated the signalling activation by immunohistochemistry at 6 months old. We discovered LRRK2 KO and G2019S KI alter Wnt signalling activity in several brain regions including the PD important striatum. mRNA and protein expression level analysis in selected brain regions showed a region specific dysregulation of Wnt signalling cascade components, the dysregulation was differed between male and female mice./ We discovered Wnt and NFAT signalling activity might be higher in glial cells than neurons in primary culture experiment, which lead us to put our focus on astrocytes. LRRK2 KO and G2019S mutation caused changes in Wnt and NFAT signalling activities in astrocytes under basal and stimulated conditions. These differences were reflected in mRNA expression levels of signalling mediators./ Taken together, these data suggest astrocytes might hold a key insight towards a better understanding of the correlation between Wnt signalling dysregulation and PD progression.

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