Induced pluripotent stem cell (iPSC)-derived 3D cortical organoid models to study dementia in Parkinson’s

Lead supervisor: Professor Richard Wade-Martins

Co-supervisor: Dr Emma Mead

Commercial partner: GSK

Parkinson’s disease (PD) is the second most common neurodegenerative disorder but disease-modifying therapies are still lacking. Dementia remains the major unmet need in Parkinson’s requiring novel targets, with most Parkinson’s patients developing dementia by ten years post-diagnosis as pathology spreads across the brain. Lysosomal biology is key to Parkinson’s, as evidenced by familial mutations, exome resequencing of idiopathic patients, and cell biology, which suggests that lysosomal dysfunction may underlie the progression to Parkinson’s disease dementia (PDD).

Human induced pluripotent stem cell (iPSC) models have revolutionised the study of neurodegenerative diseases in which the critical cell type was previously inaccessible. The Wade-Martins Laboratory has extensively characterised phenotypes in Parkinson’s iPSC models with access to >200 lines from genetic and sporadic Parkinson’s, and controls.

To develop a new iPSC-derived cortical organoid model of dementia in Parkinson’s, we propose three Specific Aims:

Aim 1: We will develop a new 3D iPSC-cortical organoid model based on techniques in routine use in the Wade-Martins Laboratory to enhance the physiological relevance of the work. Organoids will be thoroughly characterised over a prolonged period (>100 days in culture) to create an aged model relevant to disease. GSK will undertake data analysis to compare aged human brain data sets with aged organoids to characterise the model, generated initially from control iPSC lines.

Aim 2: Approximately 10% of Parkinson’s patients carry variants in the GBA1 gene encoding the lysosomal protein glucocerebrosidase, and are at higher risk of dementia. We will generate iPSC-cortical organoids from patients with the two most common Parkinson’s GBA1 mutations (GBA-N370S and GBA-L444P) to investigate lysosomal dysfunction in PDD and assay autophagy, endolysosomal function and alpha-synuclein cellular pathology, compared to age and sex-matched control cells.

Aim 3: We will exploit the exceptionally well-phenotyped Oxford Parkinson’s Disease Centre Discovery Cohort of 1000 Parkinson’s patients to compare the cell biology of iPSC-cortical organoids from idiopathic Parkinson’s patients who developed dementia later in life, with those who did not. Exploiting the rich resource of iPSC lines available in house, we will compare iPSC-cortical organoids from 6 PDD patients, 6 PD patients and 6 age and sex-matched controls, focussed on assays of autophagy, endolysosomal function and alpha-synuclein cellular pathology. Data obtained from aged Parkinson’s iPSC-cortical organoids will be compared to human brain derived datasets to understand pathobiological mechanisms in PDD. 

Priority areas: This work aligns with GSK’s priority of dementia as an unmet need in Parkinson’s and with the Oxford/GSK Institute for Cellular and Computational Medicine. The project addresses strategic priorities of accelerated drug discovery and translational development. The work is highly aligned with MRC strategic priorities by benefiting the public by identifying new drug targets and also serves the wider scientific community by increasing our understanding of the molecular pathways in dementia in Parkinson’s disease.

Environment: The Wade-Martins Laboratory provides a strong and supportive environment to undertake a DPhil within the new multidisciplinary Kavli Institute for Nanoscience Discovery. The industrial partner project supervisor Dr Lisa Mohamet provides extensive experience in target and drug discovery at leading pharma company GSK.

Apply using course: DPhil in Physiology, Anatomy and Genetics