Edinburgh Research Explorer

Dr Andy Gill

Group Leader/Senior Research Fellow

Profile photo

Phone: +44 (0)131 651 9121

Willingness to take Ph.D. students: Yes

Education / Academic qualification

Bachelor of Science, University of Warwick
Chemistry with Medicinal Chemistry
Doctor of Philosophy (PhD), University of Warwick
An investigation of the structure of ions in the gas phase
Bachelor of Science

Area of Expertise

Research expertiseProteomics, Protein misfolding


Dr Andrew Gill is a biochemist with over 20 years research experience in the field of proteomics and the determination of protein structure.

Following a degree and PhD in biological chemistry, Dr Gill joined the Institute for Animal Health, Compton as a post doctoral research scientist, before becoming a senior post-doc and then a group leader at the same institution. In 2007 Dr Gill transferred to The Roslin Insititute where he leads a team researching prion diseases and oversees the proteomics and metabolomics facility.

Dr Gill has been involved in many studies of the structure and function of diverse proteins derived from pathogens including bacteria, viruses and parasites, as well as mammalian and avian host species. Dr Gill has published widely in the fields of prion diseases and mass spectrometry/proteomics, regularly reviews articles for journals in both fields and has been part of a recent DEFRA scientific review panel. Dr Gill is an Academic Editor for Plos One, an associate editor for Frontiers in Molecular Bioscience and has been part of the grant review systems for MRC, BBSRC, APRI and FWO (Flanders).

Research Interests

Dr Gill’s core research focuses on defining how modifications to the primary and secondary structures of the prion protein contribute to prion protein function, prion protein structure and to the prion diseases that result when the prion protein misfolds. Dr Gill has defined specific structural motifs in the N-terminal region of the prion protein, a region previously thought to be unstructured, and contributed to the first crystal structure of recombinant prion protein. Recently, work has focussed on determining effects of polymorphisms of the prion gene on structural properties of the protein, based on assays to assess the propensity of protein to misfold. By assessing how cellular fractions aid the misfolding process, Dr Gill has identified subsets of molecules that potentially represent prion protein misfolding cofactors; one such cofactor is linked to prion protein function. Dr Gill is also interested in the normal function of the prion protein and in defining the repertoire of proteins whose expression levels depend on correct prion protein expression. A feature of Dr Gill's research is the application of diverse biochemical assays as well as multiple molecular dynamics simulations to understand protein structure. Dr Gill’s graduate training was in protein analysis by mass spectrometry, thereby initiating a long standing interest in the application of mass spectrometric and proteomic methods to the analysis of protein structure in general. As such, Dr Gill retains an interest in the application of mass spectrometric techniques to understand protein structure and interactions. More recently, Dr Gill has widened the use of mass spectrometric methods in biochemical analysis to encompass quantitation of specific metabolites in animal tissues.

Collaborative Activity

Helen Sang / David Hume, The Roslin Institute, University of Edinburgh - Expression and purification of exogenous proteins expressed in chicken eggs

Tom Burdon / Simone Meddle, The Roslin Institute, University of Edinburgh - Quantitation of neurochemicals in rat brain

Ian Dunn / Mark Stevens, The Roslin Institute, University of Edinburgh - Optimising ovodefensins

Fiona Houston, The Roslin Institute, University of Edinburgh - Determining why makes prion-infected blood  can transmit disease

Cheryl Ashworth, The Roslin Institute, University of Edinburgh - Proteomics of porcine ovarian follicular fluid

Rona Barron, The Roslin Institute, University of Edinburgh - Defining prion protein misfolding pathways

Wilfred Goldmann, The Roslin Institute, University of Edinburgh - The role of amino acid changes in prion protein structure, function and misfolding

Pedro Piccardo, The Roslin Institute, University of Edinburgh - Understanding the molecular causes and consequences of idiopathic brain stem chromatolysis in cattle

Alison Green, Centre for Clinical Brain Sciences, University of Edinburgh - Optimising a prion diagnostic assay

Giles Hardingham, Institute for Integrative Physiology, University of Edinburgh - Mechanisms of cell death in prion diseases


Research students

As Primary Supervisor

Mr Andrew Castle - Identification of molecules involved in prion protein function


As Secondary or Co-Supervisor

Miss Ciara Farren - Investigating molecular signatures of prion infection in blood

Miss Selene Jarrett - Proteomics of porcine ovarian follicular fluid

Miss Sze Ying - A role for neurosteroids in mediating the influence of prenatal stress on mood disorders in later life


Dr Gill lectures on prions and prion-like diseases as part of the final year elective course "Neurodegeneration, obesity and cancer" as well as covering similar ground with Neuroscience MSc students

My research in a nutshell

TSE diseases are illnesses which affect the brain, and include Mad Cow Disease (BSE), CJD in humans, and Scrapie in sheep. These diseases impair the physical co-ordination and mental capability of the host and lead inextricably to death.
TSEs are caused by build up of proteins in the brain. These proteins have folded from their normal shapes in harmful, abnormal shapes. Andy Gill and his group are investigating why this happens and how to stop it happening. 
In order to investigate this, Andy uses bacteria to produce the proteins in the lab. Sophisticated instruments are then used to analyse the abnormal proteins, and identify their shapes. These are then compared to the proteins found in the non-disease brain.

Current Research Interests

The prion protein is central to a range of diseases known as transmissible spongiform encephalopathies (TSEs for short, but also called prion diseases). During prion disease, the prion protein misfolds into aberrant conformations that can vary in size from small oligomeric forms to large plaques and amyloid fibrils. Thus, prion diseases are one of a wider class of diseases known as protein misfolding disorders and these also include Alzheimer's disease, Parkinson's disease and motor neuron disease. In all such diseases proteinaceous deposits are formed and,  concommitantly, there is also loss of specific populations of neurons. It is a distinct possibility that the build up of misfolded protein is directly toxic to neurons, but it is also possible that loss of the function of the protein that misfolds (since the misfolded form is not functional) also causes toxicity. All protein misfolding diseases have been associated with genetic alterations that appear directly to cause disease and a key question is how such changes, which correlate to amino acid changes in proteins, can initiate the different disease processes. For prion diseases, amino acid changes in the prion protein may lead to increased levels of misfolding of the prion protein or may reduce the function of the normal form of the protein. Our work is aimed at investigating both possiblities.

1. Quantifying the effect of amino acid changes on folding and misfolding pathways

We have recently focussed on uncovering the role of several key amino acids in the prion protein in determining misfolding mechanisms and are currently investigating whether the amino acid that is encoded at each position is important to direct misfolding down different pathways. We have quantitative assys for formation of different-sized oligomers and for the formation of amyloid fibrils. We also have quantiative assays for measuing the effect of amino acid changes on the structural stability of the protein. We have focussed initially on those amino acids that are known to confer resistance/susceptiblity to prion diseases in humans and anaimals, including codon 141 (susceptiblity to atypical scrapie in sheep), codon 164 (associated with resistance in sheep) and codons 169/173 (potentially associated with susceptibility to disease in deer). The aim is to define all amino acids that are important in directing misfolding down specific pathways. These studies are backed up by molecular dynamics simulations using packages such as AMBER. Current lines of research are aimed at understanding how modifications to specific amino acids quantitatively affect misfodling pathways

2. Defining whether prion protein isoforms are toxic

At the same time as determining important amino acids in directing misfolding, we need to know which misfolded forms are important during disease. For instance, amyloid fibrils have been postulated to be the benign end-point of the misfolding process, whereas smaller, oligomeric forms may be more toxic. Using primary neuronal cultures we are assessing the ability of different in vitro-generated protein isforms to elicit toxic responses. Assuming we can identify isoforms that are more toxic than others, we also need a means of detecting those isoforms in tissue samples. It has proved difficult to generate reagents that recognise specific misfolded forms of the prion protein and we are currently exploring whether biophysical separation tools can be used to produce homogeneous samples of "olgomers" or "fibrils" from in vivo sources.

3. What is the true function of the prion protein?

We are interested in determining whether loss of prion protein function contributes to prion disease pathogenesis. Even if it doesn't, manipulating the function of the prion protein may be a useful way of benefitting humans and animals, depending what its role actually is in the cell. Various lines of evidence point to an important role for prion protein in neuronal protection, but the molecular details of these properties have yet to be fully elucidated. We previously generated a list of proteins/genes whose expression changes as a result of prion protein knockout in mice. Using cell cultures that have been transfected to express murine prion protein, we are investigating whether any of our list of differnetially expressed proteins are invovled in prion protein-mediated neuro-protection. Our most recent findings suggest that the prion protein is not robustly associated with neuroprotection and, instead, we have proteomic results consistent with a top level role in regulating the response to growth factors. These findings are being followed up actively.

4. Does variation in translation efficiency effect prion protein misfolding?

There is a range of recent data that suggests that altering the speed of translation of particular proteins can impact the extent to which they carries post translational modifications as well as the fidelity of protein folding. Proteins are synthesised by ribosomes and it is clear that the initial steps of protein folding take place whilst the nascent chain is still tethered to the ribosome. Hence, in order to understand the role that variation in translation palys in causing protein misfolding, one must first understand how translation of specific proteins are regulated at the ribosomal level. We have a programme of work that aims to correlate properties and abundances of ribosomal proteins with expression levels and translation rates of individual proteins. As well as beginning to understand the role played by ribosomal protein folding in neurodegenerative diseases, this area of work will also contribute to understanding post-transcriptional regulation of protein levels.

5. Understanding protein structure and function

As a hub for protein chenistry at The Rolsin Institute, we undertake a large ammount of work to characterise proteins (and small molecule metabolites) derived from a variety of pathogens as well as the animal hosts that they attack. For example, we have recently investigated metabolic changes that are caused by knockout of the HPRT1 gene in rats, we have determined structural aspects of the recognition of Theileria-derived peptides by CD8 T-cells and we are currently investigating some of the mechanisms by which proteins are taken up by bacteria as a prelude to harnessing such mechanisms in the generation of new antimicrobials.

Highlighted research outputs

  1. The crystal structure of the globular domain of sheep prion protein

    Research output: Contribution to journalArticle

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Research activities & awards

  1. Archives of Virology

    Activity: Editorial work or peer review of publicationsPublication peer-review

  2. Antiviral Chemistry and Chemotherapy

    Activity: Editorial work or peer review of publicationsPublication peer-review

  3. Frontiers in Molecular Biosciences

    Activity: Editorial work or peer review of publicationsEditorial activity

View all (13) »

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