Regulation of dense-core vesicle function and its role in dementia

Details

Applications are invited for a fully funded PhD studentship in the laboratories of Prof Kurt De Vos (http://sitran.org/people/devos/) and Dr Elizabeth Seward (https://www.sheffield.ac.uk/biosciences/people/academic-staff/elizabeth-seward) in the Neuroscience Institute at the University of Sheffield. 

Dysfunction and degeneration of synapses (synaptopathy) is a common feature in many neurodegenerative diseases. Because synaptic impairment precedes axon degeneration and progresses through a ‘dying-back’ mechanism, it is likely that synaptopathy is not just a secondary manifestation to neuron loss but rather plays an active role in pathogenesis.

Neuropeptides, neurotrophins, and other signalling molecules, together referred to as neuromodulators, are secreted from both synaptic and extrasynaptic sites and mediate direct neurotransmission, neuromodulation, and endocrine functions, such as neuroprotection, axon growth and synaptic plasticity. Neuromodulators are stored and transported in dense-core vesicles (DCVs) prior to regulated release. Disruption to neuropeptide signalling has been implicated in numerous neurodegenerative disorders.

In this project we will investigate the role of DCV dynamics and neuromodulator secretion in the most common familial form of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), caused by mutations in the C9orf72 gene. 

The prospective PhD student will examine DCV generation, docking, priming and fusion in cell models, study a novel molecular pathway regulating DVC function and determine the contribution of disrupted DCV function in C9orf72-related FTD/ALS

This project uses state-of-the-art microscopy, physiological, biochemistry and molecular biology approaches, including the use of CRISPR/Cas9, electrophysiology, proximity ligation assays, and super-resolution fluorescence microscopy.

Interviews will likely be held in April. Students must be able to start by October 2023. 

Applications are open to students from both the UK and overseas, though we note that due to funding constraints the availability of positions for students with overseas fee status will be more limited. We anticipate competition for these studentships to be very intense. We would expect applicants to have an excellent undergraduate degree in a relevant discipline. We would also expect applicants to have completed or be undertaking a relevant master’s degree to a similar very high standard (or have equivalent research experience).