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EASTBIO The role(s) of translation elongation factors in specific neuronal populations throughout the lifecourse

  • Full or part time

    Prof I Stansfield
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Translation elongation factor eEF1A plays a pivotal role in the elongation step of protein synthesis, delivering the amino-acylated tRNA to the ribosome in a GTP dependent process facilitated by the eEF1B complex; eEF1A and eEF1B subunits together make up the eEF1 complex. Although most translation factors are ubiquitously expressed, eEF1A is found in vertebrates as two independently encoded, 92% identical variants with non-overlapping expression patterns. eEF1A1 is expressed ubiquitously throughout development, but after birth is gradually downregulated to undetectable levels in neurons and muscle (both cardiac and skeletal). Mutations in eEF1A2 or in individual members of the eEF1B complex result in neurodevelopmental disorders and have been implicated in neurodegeneration.

In spite of much work on translation elongation there is still a great deal we don’t understand about the roles specific components of the eEF1 complex play in the brain, and how expression of specific variants changes at different developmental stages in specific subtypes of neurons. Much of the current understanding is extrapolated from yeast, but this obviously limits us in terms of understanding cell specificity. We know, of course, that translational control is an essential part of synaptic plasticity, so apparently small changes in the composition of the translational apparatus from neuron to neuron or at different developmental stages could have a major impact on neuronal networks and correct functioning of the brain.

In the first part of this project the student will build a comprehensive map of expression of translation elongation factor eEF1 subunits in the brains of young and old mice both in terms of specific neuronal populations and changes in subcellular localisation within given neurons with age. This aspect will be facilitated by the availability of a mouse line in which we have genetically engineered an epitope tag into the endogenous eEF1A2 gene. The second part of the project will be more hypothesis driven, using physiological perturbations of eEF1 factors to address questions that emerge from the student’s work in the earlier stages of the project. These could include studies on the functional consequences of the eEF1A switch, whether switching is related in any way to codon usage, and/or how the switch between eEF1A variants relates to expression of eEF1B subunits.

This project will provide research training in molecular neuroscience, mouse genetics and microscopy.

Download application and reference forms via: http://www.eastscotbiodtp.ac.uk/how-apply-0

Applications: Completed application form along with your supporting documents should be sent to our PGR student team at

References: Please send the reference request form to two referees. Completed forms for this IGMM project should be returned to by the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.

References

References:
1. McLachlan, F., A.M. Sires, and C.M. Abbott, The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders. Hum Mutat, 2019. 40(2): p. 131-141.
2. Kapur, M. and S.L. Ackerman, mRNA Translation Gone Awry: Translation Fidelity and Neurological Disease. Trends Genet, 2018. 34(3): p. 218-231.
3. Sasikumar, A.N., W.B. Perez, and T.G. Kinzy, The many roles of the eukaryotic elongation factor 1 complex. Wiley Interdiscip Rev RNA, 2012. 3(4): p. 543-55.

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