Genetic Architecture of Glial Responses to α-Synuclein Pathology in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α-synuclein into Lewy bodies and neurites. Increasing evidence indicates that neuroglia (microglia, astrocytes, and oligodendrocytes) actively contribute to PD pathogenesis via neuroinflammation, proteostasis failure, and α-synuclein propagation. Genome-wide association studies (GWAS) have identified >140 PD risk loci, but the cell types, regulatory programs, and mechanisms through which many of these loci act remain poorly understood. Tools such as gsMap can integrate GWAS summary statistics with cell-type-specific epigenomic and transcriptomic data to assign risk variants to likely effector cell types, including specific glial subpopulations.

Human iPSC-derived microglia cultures and midbrain organoids offer physiologically relevant systems to model glial–neuronal interactions in the context of α-synuclein pathology. Combining computational mapping with single-cell transcriptomics of α-synuclein-exposed glial models enables direct experimental interrogation of genetically informed pathways.

1. Map PD genetic risk to glial cell subtypes using GWAS summary statistics and integrative functional genomics.

2. Experimentally model α-synuclein–induced glial responses using human iPSC-derived microglia cultures and midbrain organoids.

3. Profile glial transcriptional states at single-cell resolution and integrate with genetic mapping results to identify and prioritise candidate pathogenic pathways.

Approach and Timeline

Year 1 – Computational mapping and model setup

• Analyse publicly available PD GWAS data using gsMap, LDSC-SEG, and TWAS to identify glial-enriched risk loci.

• Integrate with public single-cell and epigenomic datasets to prioritise candidate genes/pathways.
• Work with Dr Nayler to establish iPSC-derived microglia and midbrain organoid cultures.

Year 2 – Experimental perturbation and single-cell profiling

• Expose microglia cultures and organoids to pre-formed α-synuclein fibrils to model extracellular Lewy body pathology.
• Perform single-cell RNA-seq and, where feasible, spatial transcriptomics at early and late exposure timepoints.

Year 3 – Data integration and validation

• Integrate experimental single-cell data with GWAS mapping to find convergence between genetic risk and α-synuclein-responsive transcriptional programs.

• Functionally validate top candidate pathways (e.g., CRISPR knockdown, small-molecule modulation) in microglia/organoid models, assessing effects on neuronal survival, α-synuclein clearance, and inflammatory signalling.

Impact

This integrative project will link PD genetic architecture to human glial responses in disease-relevant models, uncovering cell-type-specific mechanisms and therapeutic targets that cannot be identified by computational or experimental approaches alone.

Training Outcomes

The candidate will gain advanced bioinformatics skills in GWAS integration, single-cell data analysis, and network/pathway modelling, alongside wet-lab expertise in iPSC-derived microglia/organoid culture, α-synuclein pathology modelling, and single-cell genomics.