My project here in the Wade-Martins research group focuses on a number of transgenic rodent lines which express either mutant or wild type forms of the human Leucine-rich repeat kinase 2 (LRRK2) protein within a bacterial artificial chromosome (BAC), previously generated by the laboratory. Mutations in the LRRK2 encoding gene are the most common cause of monogenic Parkinson's Disease (PD). The identification of polymorphisms in LRRK2 associated with increased risk for sporadic PD, as well as the observation that LRRK2-PD has an almost indistinguishable pathological phenotype from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic PD cases. An age-dependent decrease in striatal dopamine signalling, in the absence of nigro-striatal degeneration, has previously been described in these animals, as well as late-stage motor and non-motor behavioural phenotypes, specific to the G2019S and R1441C mutations, reminiscent of PD.
Consequently, in order to account for the deficiencies observed in these rats, my research aims to explore the cellular consequences of LRRK2 mutations in these animals, utilising both in vivo and in vitro methods. My primary focus for the initial stages of my project are the effects of mutant LRRK2 on signalling pathways in which the wild type form has already been implicated; autophagy, intracellular trafficking, neurite outgrowth and endo/exocytosis. In doing so, we hope to obtain an understanding of the mechanisms of mutant LRRK2 which subsequently lead to the cellular and behavioural phenotypes previously described in these animals, and therefore gain insight into those which underlie the early, pre-motor, dysregulations in PD which are a sought after target for future neuroprotective treatments.
After obtaining my BSc in Psychology from Royal Holloway University of London in 2013, I was accepted on to the Clinical Neuroscience MSc course at the Institute of Neurology, UCL. My research here, in association with the Reta Lila Weston Institute of Neurological Studies, focused on the role of oxidative stress as a regulator of LRRK2 function. There after I was awarded the Pitts-Tucker studentship in 2014, for which I am extremely grateful, in association with my current three year DPhil.