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Biochemistry

Led by Dr Ben Abell, the Biochemistry Research Group carries out research in the following areas.

Parkinson's disease (PD)

PD occurs in 0.17% of the general population affecting ~1 to 2 per cent of those over 80 years old. Although rare heritable forms of PD have been documented, the sporadic form is far more common and this is possibly connected to environmental factors. The molecular mechanisms of neurodegeneration in PD are mostly unknown and the lack of preventative treatments for PD is undoubtedly a result of our limited understanding of the underlying aetiology. A critical step is the formation of Lewy bodies, in which alpha-synuclein in the form of amyloid-like aggregates has been identified as a major component. Soluble alpha-synuclein oligomers populated during amyloid assembly have been implicated as the causative agent in PD.

Dr David Smith is carrying out research within the centre, focussing on linking the structural properties of amyloid oligomers thought to be responsible for cell death to their toxic mechanism. Ion-mobility-spectrometry mass-spectrometry is used to characterise the size and shape of these oligomeric species.

Ion mobility mass spectrometry of non-covalent complexes

Dr Smith also carries out research using electrospray ionisation - ion mobility spectrometry - mass spectrometry (ESI-IMS-MS). This is an emerging technique which can be utilised to characterise the conformational states of monomeric proteins and large non-covalent complexes. ESI-IMS-MS has the unique advantage of allowing the structural characterisation of transient non-covalent protein complexes and co-populated conformational states to be monitored in real time.

Detailed knowledge of the tertiary and quaternary structure of proteins and protein complexes is of immense importance in understanding their functionality. Similarly, variations in the conformational states of proteins underlie many biomolecular processes, numerous of which are disease-related, for example, cystic fibrosis, some forms of cancer, and the amyloid diseases including Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease.

Control of translation initiation in response to stress conditions in the budding yeast Saccharomyces cerevisiae

We are interested in how the localisation of factors involved in the translation initiation pathway impact upon the control of translation initiation. We have identified that both eIF2B and eIF2 localise to a cytoplasmic body termed ‘the eIF2B body’. Evidence from live cell imaging techniques such as FRAP (fluorescent recovery after photobleaching) suggest that eIF2 shuttles between the cytoplasm and these bodies, and that this rate of shuttling alters in response to stresses which directly target the eIF2B exchange reaction.

Therefore these eIF2B bodies maybe sites where eIF2B catalyses the exchange of inactive eIF2-GDP for active eIF2-GTP and therefore form centres within the cells for the regulation of translation initiation. Future studies will aim to determine the precise function, structure and requirement for the eIF2B body within yeast cells. These studies are led by Dr Susan Campbell.

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