Theme 2: Cellular and genetic models

In Theme 2 we are building on our knowledge of the genetics underlying Parkinson's to understand the molecular mechanisms of disease using human patient stem cell-derived neuronal and glial models. The genetic variations predisposing to PD are numerous, and there is growing evidence that many of the known variants act in common biological pathways and processes. We use unique approaches developed by members of the OPDC to identify such pathways and the convergent action by which genetic variants may cause disease, both individually and cumulatively.

The OPDC has generated over 200 induced pluripotent stem cell (iPSC) lines from a range of subjects, including monogenic and idiopathic PD, and healthy controls. We have established a differentiation platform to generate functional and highly physiological midbrain dopamine neurons from iPSC lines (iPSC DA neurons), as well as microglia and astrocytes. This work provides a neurophysiologically-defined model of previously inaccessible vulnerable SNc dopamine neurons and surrounding glia to bridge the gap between clinical PD and animal models.

• Building on our exome resequencing, SNP genotyping and pathway-based analyses, we are using genetic modelling of extreme clinical phenotypes in the OPDC and Tracking Parkinson’s cohorts to increase power to detect variants predisposing to PD occurrence and subtype.
• Phenotypic analysis of iPSC DA neurons from patients with extreme phenotypes, such as rapid progression to dementia, will inform on molecular mechanisms at play in different forms of disease.
• A major strength in the OPDC program lies in our ability to generate hypotheses from bioinformatics pathway analysis of RNA Seq transcriptomics and proteomics to predict potential therapeutic targets which can be tested in patient neurons.
• Deep phenotyping of our rich resource of Parkinson's patient iPSC DA neurons generated by OPDC and our partner StemBANCC provides rationale for target discovery assay design.
• Phenotypes previously revealed in GBA, LRRK2, SNCA and sporadic Parkinson's iPSC DA neurons are used in high-throughput phenotype-driven screens to identify novel targets and repositionable drugs.
• iPSC-derived glial models, such as microglia and astrocytes, provide insight into non-neuronal mechanisms of disease and provide opportunities to identify non-neuronal therapeutic targets.