Development of a Human Cholinergic Co-culture Model to Investigate α-Synuclein-Induced Neurodegeneration in Parkinson’s Disease Dementia and Dementia with Lewy Bodies

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Neurodegenerative diseases represent one of the greatest biomedical challenges of the 21st century. Parkinson’s disease dementia (PDD) and Dementia with Lewy Bodies (DLB) affect millions worldwide and remain without disease-modifying therapies. While Parkinson’s disease is traditionally associated with the loss of dopamine-producing neurons, it is now recognised that degeneration of cholinergic neurons in the basal forebrain is the strongest predictor of cognitive decline and dementia. Despite this, the mechanisms driving cholinergic vulnerability remain poorly understood because most laboratory models focus almost exclusively on dopaminergic neurons.

This exciting PhD project will address this critical knowledge gap by developing one of the first advanced human cholinergic neuroglial models to investigate how toxic α-synuclein oligomers drive neurodegeneration. Working at the interface of neuroscience, cell biology and translational medicine, the successful candidate will generate innovative human cell models that have the potential to transform our understanding of cognitive impairment in Lewy body disorders while providing a powerful platform for future therapeutic discovery.

Based within the Pienaar Laboratory at the University of Birmingham, the student will establish differentiated human cholinergic-like neuronal cultures and integrate these with human microglia and astrocytes to create physiologically relevant co-culture systems that better reflect the complexity of the human brain. These models will be used to determine how α-synuclein oligomers disrupt neuronal communication, trigger inflammatory responses and impair the cellular pathways responsible for maintaining healthy brain function.

The project will investigate several fundamental mechanisms believed to contribute to neurodegeneration, including mitochondrial dysfunction, calcium dysregulation, oxidative and endoplasmic reticulum stress, autophagy-lysosomal failure, neuroinflammatory signalling, tau pathology and the propagation of α-synuclein between brain cells. The student will also examine how these processes interact to produce selective cholinergic degeneration and identify early molecular changes that occur before irreversible neuronal loss.

A major strength of this project is its multidisciplinary training. The successful applicant will gain extensive experience in cutting-edge experimental techniques, including human neuronal cell culture, neuroglial co-culture systems, high-content fluorescence imaging, confocal microscopy, live-cell calcium imaging, immunocytochemistry, molecular biology, phosphoproteomics, mitochondrial bioenergetics, quantitative image analysis and biochemical assays of cholinergic neurotransmission. The student will also receive training in experimental design, advanced statistical analysis, scientific communication and research reproducibility, providing a comprehensive skill set that is highly sought after in both academia and the biotechnology and pharmaceutical sectors.

Importantly, this project extends beyond understanding disease mechanisms. Using mechanistic insights generated throughout the study, the student will evaluate novel neuroprotective strategies aimed at restoring cholinergic function and neuronal survival. Candidate therapeutics will include compounds that enhance autophagy, protect mitochondrial function, modulate cholinergic signalling and inhibit α-synuclein aggregation, creating opportunities to contribute directly to the development of future treatments for dementia.

This project offers excellent opportunities for publication in high-impact international journals and presentation of findings at national and international neuroscience conferences. The student will work within a vibrant and collaborative research environment with opportunities to engage with clinicians, neuroscientists and international collaborators, developing a professional network that supports future career progression.

This PhD is ideally suited to highly motivated students with a background in neuroscience, biomedical sciences, pharmacology, cell biology or a related discipline who are passionate about understanding brain disease and developing innovative experimental models with genuine translational potential. Graduates from this project will be exceptionally well positioned for careers in academic research, the pharmaceutical and biotechnology industries, contract research organisations or further translational neuroscience research.

By helping to develop one of the first comprehensive human cholinergic models of Lewy body dementia, the successful candidate will make a meaningful contribution towards understanding the biological basis of cognitive decline while acquiring advanced technical expertise and producing research with the potential to influence the next generation of therapies for Parkinson’s disease dementia and Dementia with Lewy Bodies.

To apply:

Please send your enquiry and CV to the Lead Supervisor, Dr. Ilse Pienaar, at i.pienaar@bham.ac.uk.