Postdoctoral Research Fellow, Junior Research Fellow Kellogg College
My work in the Wade-Martins lab 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) 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 two main projects:
Bulk and single cell transcriptomic analysis of dopamine neurons from patients with PD, 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. This project is in collaboration with Caleb Webber’s computational group in Cardiff and the Oxford genomics centre at the Wellcome Centre for Human Genetics in Oxford.
NRF2 dysfunction in iPSC-derived astrocyte and iPSC-derived dopamine neuron models of PD
Nrf2 is a master regulator of cytoprotective responses and has previously been implicated as neuroprotective in PD. In oxidative stress conditions (which are well known to occur in PD) Nrf2 translocates to the nucleus where it initiates the transcription of anti-oxidant and other cytoptrotective factors. Which cell type is more crucial in these actions is still not well understood. Therefore, this project invovles differentiating iPSCs from patients with different types of PD mutations (GBA-N370S, SNCA-A53T, SNCA Triplication, LRRK2-G2019S and LRRK2-R1441C) into both astrocytes and dopamine neurons, to identify whether any PD disease-relevant phenotypes in these cell types can be rescued by Nrf2 activation. This project is in collaboration with AstraZeneca Neuroscience.
What we can learn from iPSC-derived cellular models of Parkinson's disease.
Caiazza MC. et al, (2020), 252, 3 - 25
Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons.
Zambon F. et al, (2019), Hum Mol Genet, 28, 2001 - 2013
Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes.
Lang C. et al, (2019), Cell Stem Cell, 24, 93 - 106.e6
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
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, nanopore 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.