Ageing and Neurodegeneration - a zebrafish study

Ageing is the single biggest risk factor for all neurodegenerative disorders. Crucial mechanisms including DNA damage, mitochondrial dysfunction and aberrant activation of the immune system are shared features in ageing and neurodegeneration. However, the precise interplay between ageing-related mechanisms and neuronal cell death remain poorly understood. Zebrafish models of human neurodegenerative diseases can closely mimic the observed biochemical and morphological changes observed in human patients. Different mutant zebrafish strains have now also provided important “proof of principle” data which confirm that cellular senescence and accelerated ageing can be observed in zebrafish carrying mutations in ageing-related genes. Klotho deficiency is a key regulator of ageing process in humans and other vertebrates. The Bandmann lab has established a klotho-mutant zebrafish line which mirrors key hallmarks of accelerated ageing in humans and rodent models. The Bandmann and Burton labs also have a wide range of different stable mutant or transgenic zebrafish lines carrying mutations in genes which cause Parkinson’s disease (PD).

The aim of this proposal is to study the effect of ageing on key mechanisms linked to PD by crossing the klotho-mutant zebrafish line to PD gene mutant zebrafish lines. The project will particularly focus on the effect of accelerated ageing on immune mechanisms and mitochondrial function.

The Bandmann and Burton labs have considerable expertise in the use of zebrafish to study neurodegenerative disorders. The El-Khamisy lab has considerable expertise in mechanisms underlying ageing-related neuronal cell death, in particular DNA damage. The successful candidate will be trained in a wide range of techniques, including behavioural characterisation of larval and adult zebrafish, Western blots, Q-PCR, immunohistochemistry, quantification of dopaminergic neurons, toxin exposure protocols, microglial activity assays. In addition, the successful candidate will undertake in-house RNAseq analysis (including gene enrichment analysis, context analysis, pathway analysis) with close supervision by our excellent Bioinformatics group.

The student will mostly be based at the Bateson centre of the University of Sheffield (https://www.sheffield.ac.uk/bateson). The Bateson centre hosts a large number of zebrafish PIs and has a vibrant PhD student community. The student will also benefit from complementing expertise and equipment at the Sheffield Institute for Translational Neuroscience (SITraN, http://sitran.org/). The successful candidate will also have the exciting opportunity to spend 6-12 months in the lab of our US collaborator Prof Ed Burton (http://www.pind.pitt.edu/labs/burton-laboratory/).