Role of dopamine and LRRK2 mutants in Parkinson's disease

The most common genetic cause of Parkinson’s disease (PD) is a mutation in the LRRK2 gene, G2019S. We have therefore developed a new fly model, which exploits the homology of gene and visual organization between fly and human. Flies show rapid decline in electroretinogram performance with G2019S expression, but not with other mutations in LRRK2. This loss of visual function is most marked when G2019S is expressed in the dopaminergic neurons. Remarkably, when G2019S is expressed in dopaminergic neurons it is the non-dopaminergic photoreceptors which are most affected, indicating a spreading pathology. The aim is to test the hypothesis that it is the interaction between dopamine and G2019S which leads to neuronal death. The objectives are to use the extensive fly genetic toolbox to manipulate dopamine levels, to test the function of G2019S as a dominant negative kinase mutation, and to examine the role of neural activity in accelerating the speed of degeneration. This will be supported by drug application (L-DOPA, kinase inhibitors, glycolytic upregulation). Confocal microscopy will be used to examine the way in which the pathology spreads form neuron to neuron – especially focusing on dopaminergic terminals. This will provide a new view of LRRK neurophysiology in the whole organism, in a way that has not been possible in mouse models.
The student will acquire skills in fly genetics, molecular and cell biology, neurophysiology and neuropharmacology. He/She will be part of a vibrant fly community, alongside 3 other PhD students.
Students will be expected to be predicted / have a first class degree in Biology, Neuroscience, Biochemistry, Cell Biology, Physiology, Genetics or related subject. Students with 2:1 degrees and relevant experience, and suitable Masters degrees can also apply. Experience of neuroscience and /or model organisms would be appreciated.
Informal enquiries, including a CV and ½ page summary of project work should be sent to Chris Elliott ([Email Address Removed]).