Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB) are devastating neurodegenerative diseases, characterised by the accumulation and build-up of the protein alpha-synuclein (aSyn) into Lewy body aggregates. aSyn accumulation causes inflammation and, eventually, the progressive loss of brain cells. But what triggers this harmful cascade remains unclear.
This PhD project challenges the long-standing view that inflammation is merely a consequence of dying neurons. Instead, our unpublished findings suggest that neurons themselves detect aSyn accumulation as a “danger signal,” and activate immune responses long before clinical symptoms appear. We believe these early events could hold the key to preventing or slowing disease progression by protecting remaining healthy neurons after a patient is diagnosed. This project aims to identify and characterise these early immune triggers, with the goal of uncovering new targets for therapeutic intervention.
You will join an interdisciplinary team at the interface of neuroscience, immunology, and genetics. Using human neuronal cell models, you will define the immune pathways activated by pathogenic aSyn. These findings will be tested in animal models and extended to patient-derived neurons and brain tissue. AI and machine learning will help analyse complex multi-omics datasets and uncover key regulators of disease.
Training and Approach:
Year 1: Use RNA-seq and proteomics in human neuronal cells (SH-SY5Y) expressing wild-type or mutant aSyn to identify innate immune pathways upregulated in response to pathogenic aSyn. Validate key hits using CRISPR and targeted assays.
Year 2: Manipulate key pathways in Drosophila models of synucleinopathy and assess effects on behaviour, brain inflammation, and neurodegeneration.
Year 3: Extend findings to the human context by analysing iPSC-derived neurons and post-mortem brain samples. Stratify patient data using AI models to link immune activation with disease stage and genetic risk.
Year 4: Finalise data analysis, write manuscripts, and prepare the thesis. Explore translational potential with clinical collaborators at the Karolinska Institutet in Sweden.
3-month rotation project: Use SH-SY5Y cells expressing patient-derived aSyn variants to profile inflammatory responses by RT-qPCR, ELISA, western blotting, and microscopy. The rotation project offers a springboard into the full PhD project.
Skills and techniques: RNA-seq, proteomics, CRISPR, cell culture, microscopy, animal behaviour, and bioinformatics (including AI).
Significance:
By investigating how neurons themselves trigger inflammation, this project aims to redefine the earliest molecular events in PD and DLB. The findings could identify new therapeutic targets to intervene before irreversible damage occurs, offering insights for disease-modifying treatments.