(BBSRC DTP) The evolution of nerves: understanding the roots of neurodegeneration

Axons are the cable-like extensions of neurons which can be up to a meter long and form the nerves that wire our nervous system. In humans, axons have to survive for up to a century; unsurprisingly, we lose ~40% of axons towards high age - and many more in neurodegeneration.

To understand long-term maintenance of axons, we focus on the bundles of microtubules that run all along axons in invertebrates and humans alike [Ref. 2]. These bundles determine axon structure and form the highways for life-sustaining axonal transport. Importantly, axon degeneration often has its causes in microtubule bundle decay, which is why we need to understand how these bundles can be structurally maintained [Ref. 2].

From invertebrates to humans, axonal microtubules are believed to be cross-linked by microtubule-binding proteins, such as MAP1B or tau which are closely associated with neurodegeneration including Alzheimer’s. However, their linker functions are surprisingly little understood. Of particular interest is MAP1B, which shows an unusual evolutionary profile: some regions are well conserved from crustaceans to humans, whereas others are highly variable and often unrecognisable already between species of the same family [Fig. S1 in Ref. 2]. Studying the evolutionary similarities and differences between MAP1B proteins in diverse species offers opportunities to understand linker functions, how changes in their sequences can generate different neuron morphologies, and also provide explanations for neurodegenerative processes.

For this, we will capitalise on MR’s expertise in evolutionary biology (see web-link below) to perform phylogenetic analyses of MAP1B and its homologues, aiming to extract concepts and rules that explain MAP1B’s evolutionary behaviour, and develop experimentally testable working hypotheses. Experiments will build on AP’s expertise on axon structure and microtubule regulation using Drosophila neurons as a genetically amenable system for fast and efficient experimentation [Refs. 1-3]; thus, we will modify the fly MAP1B gene to test our phylogenetics-derived hypotheses. Many experiments will involve electron microscopy (EM) for which KK is a long-standing expert (see web-link below); EM will reveal structural aberrations, subcellular positions of MAP1B and changes in microtubule spacing.

Taken together, this is a highly interdisciplinary project based on the joined expertise of three experienced PIs. It will provide training opportunities across genetics, phylogenetic analysis, molecular biology, biochemistry, cell biology and electron microscopy, and in-depth introduction to concepts of evolution, cytoskeletal regulation and neurodegeneration. Furthermore, AP is an expert in science communication widening the scope of transferable skills training on this project.

• www.manchester.ac.uk/research/Andreas.Prokop
• www.manchester.ac.uk/research/Karl.Kadler
• www.manchester.ac.uk/research/Matthew.Ronshaugen

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships