Parkinson’s disease: from pathological mechanisms to target discovery

Event details

Speaker: Professor Richard Wade-Martins MA DPhil (University of Oxford)

Parkinson's disease (PD) is the second most common neurodegenerative disease and a major unmet clinical need in our ageing population. The Oxford Parkinson's Disease Centre (OPDC) has since 2010 built a translational research program to understand and target the earliest pathological pathways in PD.

In the clinic we have collected 1000 PD patients, plus age-matched controls and "at-risk" individuals for an in-depth longitudinal patient phenotyping study. In the laboratory we have generated >200 induced pluripotent stem cell (iPSC) lines to derive neurons and glia from genetic (GBA, LRRK2, SNCA, PINK, PARKIN) and sporadic PD patients and controls to allow us to study cellular phenotypes in an accurate, physiologically-relevant model of dopamine neurons and glia.

We have undertaken detailed phenotypic and transcriptomic analyses of PD iPSC-derived dopamine neurons to better understand the early molecular changes which underlie cellular vulnerability in disease and to identify new targets for therapy. Our work modelling disease mechanisms has uncovered defects in the autophagic and endolysosomal pathways, in endoplasmic reticulum (ER) stress, in the biology of alpha-synuclein, and in mitochondrial activity.

Comparative transcriptomic analysis has recently allowed us to identify potential new therapeutic targets and potential therapeutic molecules. Finally, we have generated and characterised a number of highly relevant transgenic rodent models of Parkinson’s to probe disease mechanisms and act as preclinical models to trial potential disease-modifying therapies.

In addition, we have developed automated assays suitable for high-throughput screening and have completed a 4000 compound phenotypic screen in patient iPSC-derived neurons using state-of-the-art phenotyping platforms for target and drug discovery.