Parkinson’s disease is a progressive neurodegenerative disease affecting up to 1:500 people over the age of 50 years.1 The risk of developing Parkinson’s disease is multi-factorial involving environmental and genetic factors.2 One of the main genetic contributors is the leucine-rich repeat kinase 2 (LRRK2) and is implicated in both sporadic and familial forms of the disease.3 There is mounting evidence that all pathogenic LRRK2 mutations exert their effect by increasing LRRK2 kinase activity.
The penetrance of LRRK2 mutations is highly variable and at present there is no means of predicting if and when non-manifesting LRRK2 mutation carriers will develop PD. This project will investigate whether two new diagnostic approaches can predict those LRRK2 mutation carriers that will go on to develop PD.
Dr Sammler has recently reported a novel assay to measure the LRRK2 kinase pathway activity in blood neutrophils, based on the monitoring of Rab10 phosphorylation.4 This has been shown to be a robust and novel approach to assessing LRRK2 activity. Dr Green has developed a protein aggregation assay, RT-QuIC, which detects aggregated α-synuclein in cerebrospinal fluid (CSF).5
The aim of this project would be to use these two novel biomarkers to predict which LRKK2 mutation carriers go on to develop PD. A number of sample cohorts will be used: CSF (BioFIND, PPMI), and blood and CSF (Prof Eduardo Tolosa, Barcelona and Dundee).
How is the project collaborative?
This project is collaborative as the student will work in laboratories based at MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee (Dr Sammler, LRRK2 kinase activity) and at the National CJD Research & Surveillance Unit, University of Edinburgh (Dr Green, α-syn RT-QuIC). The blood and CSF cohorts will be shared between the two sites, wherever possible.
Additional Project Info
This PhD project is part of a Dundee-Edinburgh Parkinson’s Research Initiative that brings together clinicians and scientists with expertise in movement disorders, genetics, cell signalling, regenerative medicine, drug discovery, health informatics and clinical trials to enhance our understanding of the mechanisms of Parkinson’s and exploit this knowledge to develop and evaluate novel therapies in the clinic. The PhD project will be based in either Dundee or Edinburgh, but will be highly collaborative with significant interaction with the co-supervisor at the partner University.
To apply please send a cover letter, curriculum vitae and two references to: [email protected]
1. Kalia LV and Lang AE. Parkinson’s disease. Lancet 2015; 386:896-912
2. Bras J, Guerreiro R and Hardy J. Snap:Shot: Genetics of Parkinson’s disease. Cell 2015; 160:570-50 e571
3. Zimprich A, Biskup S, Leitner P et al., Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004; 44:601-607
4. Fan Y, Howden AJM, Sarhan AR et al., Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochemical J 2017;DOI10.1042/BCJ20170803
5. Fairfoul G, McGuire LI, Pal S et al., Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Trans Neurol 2016; 3(10):812-8