Identifying Novel Therapeutics for the Treatment of Alpha-Synucleinopathies: A Chemistry-Biology Approach to Parkinson's Disease

About the project

About the Project The Clinical Challenge: Parkinson's Disease and Protein Aggregation Parkinson's disease affects approximately 150,000 people in the UK and accounts for around 8,000 deaths annually. It is the second most common neurodegenerative disorder worldwide, and its prevalence is rising sharply with an ageing population. Yet despite decades of research, treatments remain purely symptomatic — no disease-modifying therapy currently exists that can slow or halt neurodegeneration. A defining molecular hallmark of Parkinson's disease, and a broader class of disorders known as alpha-synucleinopathies, is the pathological aggregation of the protein alpha-synuclein within neurons. Under normal conditions, alpha-synuclein is a soluble, intrinsically disordered protein involved in synaptic vesicle regulation. In disease, it misfolds and assembles into toxic oligomers and fibrillar aggregates — collectively termed Lewy bodies and Lewy neurites — which propagate through neural circuits and drive progressive cell death. Targeting this aggregation process directly represents one of the most promising, yet largely unrealised, therapeutic strategies in neurodegeneration. A key reason this target has proven so difficult to drug is the structural complexity and heterogeneity of alpha-synuclein aggregates, which limits the rational design of small molecule inhibitors. Novel screening platforms capable of detecting and quantifying aggregation in disease-relevant systems are therefore urgently needed to identify new chemical starting points. Our Approach: Novel Screening Meets Precision Chemistry This project capitalises on a uniquely powerful combination: a novel suite of alpha-synuclein aggregation screening assays developed by the supervisory team, integrated with state-of-the-art continuous flow synthetic chemistry for rapid compound optimisation. The Morris laboratory (secondary supervisor, Newcastle University) has developed FRET-based and cellular aggregation detection assays, complemented by direct screening against human brain tissue samples obtained from confirmed Parkinson's disease donors through the Newcastle Brain Tissue Resource. This human tissue-grounded approach provides exceptional translational validity, with hit compounds that can be validated in the very biological material in which they will ultimately need to act. It also provides access to imaging mass spectrometry and fluorescent antibody methods to confirm compound binding to alpha-synuclein aggregates in situ within tissue sections. The Sellars laboratory (primary supervisor) provides world-class expertise in continuous flow synthetic chemistry and medicinal chemistry, enabling rapid, flexible generation of compound libraries and systematic structure-activity relationship (SAR) exploration. Together, these capabilities create an end-to-end discovery platform: screen, identify, synthesise, re-screen, and optimise — at speed and scale that would be impossible through conventional batch synthesis. Training and Skills Development This is a genuinely interdisciplinary project and will provide the student with a uniquely broad skill set spanning chemistry and neuroscience. Training will include: Continuous flow chemistry and medicinal/organic synthesis Protein biochemistry: recombinant protein expression, aggregation assays, FRET-based detection Cell biology: iPSC-derived neuronal cultures, quantitative imaging, in vitro toxicity profiling Human tissue handling and neuropathology: brain tissue sectioning, immunofluorescence, imaging mass spectrometry Drug discovery principles: hit identification, SAR analysis, lead optimisation The student will be embedded in two active and well-resourced research groups at Newcastle University, with access to a Graduate School of approximately 500 postgraduate researchers, weekly Neurodegenerative Disease and Neurobiology of Ageing seminar series, and the Newcastle Brain Tissue Resource — one of the most significant neuropathological tissue collections in the UK. A modular first-year Masters/PhD structure allows students from either a chemistry or biology background to build the complementary skills they need for the interdisciplinary research programme. Ideal Candidate Profile We welcome applications from motivated graduates holding a strong degree (2:1 or above) in Chemistry, Medicinal Chemistry, Chemical Biology, Biochemistry, Neuroscience, or a closely related discipline. The project is deliberately designed to be accessible to candidates with a primary background in either chemistry or biology, as the training programme will provide the necessary complementary skills. Enthusiasm for interdisciplinary research and an interest in neurodegeneration or drug discovery are essential.

Research areas