EASTBIO Microtubule proteome during neuronal ageing

A major health problem of the elderly population is mental or cognitive decline due to the decay of brain tissues. It is crucial to understand the molecular basis for neuronal ageing as it will provide a better understanding of how the brain ages and the biology of neurodegenerative disorders as well as provide insights into potential therapeutic interventions. 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 mutations in microtubule cytoskeleton-related proteins are linked to several human neurodevelopmental disorders. Despite the central role of the microtubule, little is known about how the microtubule cytoskeleton affects 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 of key microtubule-related proteins cause premature aging of the neurons in C. elegans. We hypothesize that the microtubule cytoskeletal proteome is altered, and microtubules are post-translationally modified during neuronal ageing. In the Ly lab, a sample processing method called 'in cell digest' has been developed to obtain proteome depths of >6,000 proteins from 2,000 cells and detect hundreds of proteins and their post-translational modifications from individual cells. In this study, we aim to develop and apply this method to determine the proteomic & post-translational modification profile of the microtubule cytoskeleton in young and aged neurons of C. elegans.

The student will isolate neurons from animals and profile the microtubule neuronal proteome with cutting-edge quantitative whole-organism proteomics and in vivo fluorescent cell labeling techniques. Promising candidates will be analyzed using genetic and microscopy-based approaches to determine how they impact neuronal ageing. The student will be trained in cutting-edge mass spectrometry-based proteomics and state-of-the-art in vivo high-resolution live microscopy, image analysis tools (e.g. Image J), genetics and molecular biology techniques. Together, the student will gain experience in quantitative cell biology using the latest proteomic, genetic, and imaging tools. Additionally, this collaborative effort will allow the student to work in labs with complementary 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.

https://cheerambathurlab.co.uk/

https://dynamic-proteomes.squarespace.com

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