My work in the Wade-Martins lab (https://www.dpag.ox.ac.uk/research/wade-martins-group) is primarily on understanding the cellular and molecular mechanisms of Parkinson’s disease (PD) using patient-derived induced pluripotent stem cell (iPSC) lines. The Oxford Parkinson’s disease Centre (OPDC) (http://opdc.medsci.ox.ac.uk/home) has generated a wide-range of iPSC lines from genetic and idiopathic cases of PD and from healthy controls. I am differentiating these lines into neuronal subtypes of interest in PD and will utilise them to better understand neuronal function and dysfunction in PD. I am currently working on one main project:
Bulk and single cell transcriptomic analysis of dopamine neurons from patients with Parkinson’s Disease, identifying targets of interest and testing candidate compounds for their therapeutic potential
This project involves differentiating iPSCs from patients with different types of PD mutations (GBA-N370S, SNCA-A53T, SNCA Triplication, LRRK2-G2019S and LRRK2-R1441C) and Idiopathic PD, into dopamine neurons, the cell type most vulnerable in this disease. From this heterogeneous population i can isolate dopaminergic neurons by fluorescent activated cell sorting (FACS) and perform bulk and single cell RNA-Sequencing to identify global changes in expression in these patients compared to controls.
Using this approach is a robust and efficient way to unbiasedly uncover alterations in new unidentified proteins or pathways that may be attributed to PD that may be therapeutic targets for the disease. I then validate these potentially interesting proteins or pathways, identify compounds that may act on these targets and observe their effect on PD-related phenotypes in the iPSC lines.
This project is in collaboration with Caleb Webber’s computational group in Cardiff (https://www.cardiff.ac.uk/people/view/1150695-webber-caleb) and Rory Bowden's group from the Oxford genomics centre at the Wellcome Trust Centre for Human Genetics in Oxford (http://www.well.ox.ac.uk/ogc/about-ogc/).
Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons.
Zambon F. et al, (2019), Hum Mol Genet
Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes.
Lang C. et al, (2018), Cell Stem Cell
Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease.
Sandor C. et al, (2017), Hum Mol Genet, 26, 552 - 566
ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.
Fernandes HJR. et al, (2016), Stem Cell Reports, 6, 342 - 356
α Synuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson’s Disease?
Protter D. et al, (2012), Parkinson's Disease, 2012, 1 - 12
I am originally from Sydney, Australia, where I completed my undergraduate degree, a BSc (Hons I) at the University of New South Wales (UNSW). I then went on to complete my PhD, in the Parkinson’s disease and neurogenomics lab at the Garvan Institute of Medical Research, investigating the connection between alpha synuclein and mitochondrial dysfunction in sporadic Parkinson’s disease. In February 2015 I moved to Oxford to undertake a post-doctoral fellowship in the Richard Wade-Martins lab.
My research interests lie in the area of transcriptomics and the use of breakthrough techniques including single cell RNA-seq and 10x chromium technology, sensitive tools used to identify minute changes in gene expression. Additionally, i am interested in the downstream validation of potentially new PD-related targets and the repurposing of compounds which interact with these targets for their therapeutic potential.