PhD Project - EASTBIO Microtubule proteome during neuronal ageing

Vacancy Reference Number
Closing Date
16 Dec 2021
University of Edinburgh

A major health problem of the elderly population is mental or cognitive decline due to the decay of brain tissues. It is important to understand the molecular basis behind neuronal ageing as it will provide explanations for the decline of brain function during normal ageing as well as provide insight into the biology of neurodegenerative disorders. Microtubules, long protein polymers of alpha/beta tubulin dimers, are critical for neuron formation and function. Microtubule dysregulation is a hallmark of neurodegenerative disorders, and several human neurodevelopmental disorders are linked to mutations in microtubule cytoskeleton-related proteins. Despite the central role of the microtubule, little is known about how changes in the microtubule cytoskeleton contributes to neuronal ageing. In this project we explore the role of the microtubule cytoskeleton in neuronal ageing. The project will draw on the expertise of the Cheerambathur-lab expertise in studying microtubule function in neurons using the animal, C. elegans and Ly-lab expertise in developing novel quantitative tools to study dynamic changes in cellular proteomes.

The Cheerambathur lab has found that mutations in key microtubule-related proteins causes premature ageing of the nociceptive neuron, PVD in C. elegans. We hypothesize that microtubule cytoskeletal proteome is altered, and microtubules are post-translationally modified during PVD ageing. Recently, Ly lab developed a sample processing method, ‘in cell digest’, obtaining proteome depths of >6,000 proteins from 2,000 cells and detection of hundreds of proteins from single cells. We aim to develop and apply this method to obtain detailed proteomic profile of the microtubule cytoskeleton in developing PVD neuron in C. elegans.

The student will combine cutting-edge quantitative whole-organism proteomics with in vivo fluorescent cell labelling techniques to isolate neurons from animals and profile the microtubule neuronal proteome. Promising candidates will be analyzed using genetic and microscopy-based approaches to determine the relation of the microtubule factors and neuronal ageing. The student will also be trained state-of-the-art in vivo high-resolution live microscopy, image analysis tools (e.g. Image J), genetics and molecular biology techniques, cutting-edge mass spectrometry-based proteomics. Taken together, the student will develop experience in quantitative cell biology using the latest proteomic, genetic and imaging tools to tackle questions related to neuronal ageing. Additionally, this collaborative effort will allow the student to work in labs with complementing expertise and access the state-of-the-art research and training environment offered by the two institutions, the Wellcome Centre for Cell Biology in Edinburgh and the School of Life Sciences in Dundee.

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