Molecular mechanisms of α-synuclein aggrephagy and their dysregulation during human ageing

About the Project

Ageing is the single greatest risk factor for neurodegenerative disease. In dementia with Lewy bodies (DLB) and Parkinson’s disease, the protein α-synuclein accumulates into toxic aggregates that disrupt neuronal function and ultimately drive cell death. Although autophagy — the cell’s recycling system — has long been implicated in the removal of such aggregates, the precise molecular mechanisms that control α-synuclein clearance, and how these processes deteriorate during human ageing, remain poorly understood.

This fully funded 4-year PhD studentship will define how selective autophagy (aggrephagy) recognises and removes α-synuclein aggregates in human cells and ageing-relevant neuronal models. The project combines mechanistic cell biology, ageing research and translational neuroscience to uncover new targets for therapeutic intervention in synucleinopathies.

The student will use unique inducible fluorescent reporter systems being developed in the host laboratory that enable controlled aggregate formation and real-time quantification of their clearance. Using CRISPR/Cas9 genome editing, advanced live-cell imaging and quantitative biochemical approaches, the student will dissect the roles of core autophagy machinery and selective autophagy receptors (such as p62, NBR1, OPTN, NDP52 and TAX1BP1) in aggregate recognition and degradation. A major focus will be determining why aggrephagy efficiency declines with age.

To model age-related vulnerability, the student will establish direct conversion of human fibroblasts from young and older donors into induced neurons, preserving age-associated molecular signatures. This provides a powerful and physiologically relevant platform to investigate how ageing impacts neuronal proteostasis. In the final phase of the project, clinically relevant autophagy-activating small molecules will be tested for their ability to restore aggregate clearance in ageing-relevant neurons, laying foundations for future therapeutic development.

The project is jointly supervised by Professor Viktor Korolchuk (autophagy and ageing biology) and Dr Daniel Erskine (synucleinopathies and human neuropathology). The student will join a vibrant, collaborative neuroscience community at Newcastle University and receive training in advanced imaging, genome editing, human neuronal modelling, and experimental therapeutics.

This studentship offers an outstanding opportunity to contribute to understanding the cellular basis of age-related neurodegeneration while developing a strong platform for a career in academia, biotechnology or pharmaceutical research.