Data mining for neurodegeneration leads
19 April 2012
Professor Bob Burgoyne and Xi Chen reveal how a literature search gained momentum and led to a highly accessed paper.
What kind of work is your laboratory interested in pursuing?
We're interested in various aspects of neuronal signalling and the basic molecular mechanisms of neurotransmission.
We originally did a lot of work on mammalian cells and then switched over to the worm Caenorhabditis elegans as a model organism because we wanted to work at the organismal level and the ease of doing genetic studies. Then we became interested in C. elegans as a model for age-related neurodegeneration.
What led to your new BMC Genomics (ref 1) paper?
Our student (see 'Xi Chen' below) was doing a Master's of Research degree (MRes) in cellular and molecular physiology and MRes students do three projects in rotation. For one of these we wanted to identify a potential set of target genes in neurodegeneration [regulator genes].
We realised there was a lot of work in the literature, so the point of this project was to go through papers that have identified genes for neurodegeneration in three model organisms: Saccharomyces cerivisae (brewers' yeast), Drosophila melanogaster (fruit fly) and the worm C elegans.
Why look at three organisms?
By looking at different disease models we can identify genes that might regulate multiple types of neurodegeneration. People have tended to study single disease models, say in just C. elegans. And we're also trying to find common things in all types of neurodegeneration, in normal ageing for example.
So the idea of the project was to use the worm as a basic model and try and look at which of these neurodegeneration genes in other organisms had orthologues [variants] in worms and humans.
What were the results?
What emerged from pooling data from different studies was that 34 genes were identified which regulated different models of neurodegeneration (across yeast, flies and worms). This gave us a new set of genes that may be important, and they all have human orthologues, which means they may be important in human disease as well.
What did the 34 genes tend to do?
Different processes, like protein folding, also membrane traffic, lipid metabolism, endocytosis; lots of different process including some that we might not have thought would be important – but all genes found to effect neurodegeneration in some way or another.
Are any of the genes of particular interest?
We're interested in protein called cysteine string protein, also called dnj-14, in the worm. If this protein is mutated or knocked out it results in neurodegeneration, so the protein has a normal role in neuroprotection in ageing.
The idea is knockout the expression of other genes to see whether that would exacerbate or protect against dnj-14-relatedneurodegeneration; that will allow us to identify genes involved with neurodegeneration.
What led you down the 'data mining' approach?
The idea was to produce a list of genes for our own studies, but having done that we realised we'd generated a potentially useful resource for other people.
Is it unusual for an MRes student to produce a paper of such standing?
Yes, this is very unusual. Occasionally students contribute a smaller part to a study, but in this she is first author and the bulk of it is her work. She's an outstandingly good student. She got first class BSc in Human Anatomy from this university and came to us knowing very little about model organisms and has learnt all this very rapidly. She's now in our group doing a PhD. (Read more from Professor Burgoyne below.)
How do you feel about a successful first paper?
I am ecstatic about my first publication, this was an excellent opportunity to develop the research skills, training and expertise I needed and has further motivated me forward.
Describe the work in your own words…
I carried out an integrative analysis of available genetic regulators of neurodegeneration in three model organisms in order to get a full understanding of what key regulatory genes had already been identified to feed the information into the design of further studies.
This analysis identified a significant number of overlapping regulators of neurodegenerative disease models which all had human orthologues and we realised that the findings could be of interest to others in the scientific community and decided to publish the analysis.
What are you working on now?
With the BBSRC funding I am currently using various well characterised C. elegans models to screen for pharmacological and genetic modifiers of neurodegeneration, and exploring possible mechanisms of neurotoxicity. Additionally, we also intend to follow up the neurodegenerative disease-associated overlap we have observed.
Why are you interested in this area of science?
When I enrolled in human anatomy the hard science aspects of neuroscience fascinated me the most. The elucidation of the disease mechanisms of neurodegeneration is exploding as a field and its understanding is key to developing and taking forward new treatments.
What would you like the future impacts of you work to be?
Hopefully, any significant findings I obtained using C. elegans will be translated into mammals and would form a useful resource to be exploited in further studies of potential therapeutic targets for improved clinical treatment.
When did you first realise that you wanted to be a scientist?
I discovered science in the form of biology when I was eight and have been doing science full time for nearly fifteen years. I find all parts of science fascinating and decided to pursue it further when I was in the school sixth form.
What proteins/gene targets would now be useful for others to study?
Some have emerged which have not been studied in detail. Some we will study in more detail and others can as well to try and find how they protect against neurodegeneration. The other issue is they could be drug targets.
What are more promising drug targets?
Novel ones to look at – acyl coenzyme A – a peroxisomal enzyme [from the peroxisome organelle] is not something people have thought about in detail, and one of the things we will follow up. If we can find out about pathways in which the enzyme acts, then that gives us ideas about other drug targets as well, and which other genes might be involved.
What has been the reaction to paper?
It's in BMC Genomics where you can see data on access. It was the number four most downloaded paper in the first week and is now marked up as a highly accessed paper. We've also been contacted by other magazine editors.
This paper was funded by a BBSRC studentship. How useful this type of funding?
This was one of the BBSRC Doctoral Training Grants awarded to the University of Liverpool's School of Biomedical Science, as it was then, for students funded as an MRes followed by a PhD. It allowed us to set a project we wouldn't have normally have worked on and it gave us the opportunity to attract a very good student to work on this.
What's next for your lab's research?
We now have a new BBSRC project to work on the cysteine string protein which has a neuroprotective effect in normal ageing and development, and in another project Xi is studying various different neurodegeneration models in the worm.
Why is cysteine string protein important?
It's localised in synapses and believed to be involved with proteins in neurotransmission, but it's not entirely clear how that links to the neuroprotective effect. Some of these synapse proteins become misfolded and that may lead to neurodegeneration of the neuron.
What is the significance of protein misfolding?
One of the big arguments in neurodegeneration is about protein aggregates and plaques caused by misfolding. There is a growing feeling that the misfolding of proteins causes an abnormality in signalling between neurons, and that leads to initial defects. The neurodegeneration occurs later down the line as consequence of those earlier events.
How long have you been working on this?
I've been at this university for about 28 years now and am now in the Institute of Translational Medicine which was only formed in 2010 by merger of various other departments – its core mission is to join up basic underpinning science on, for example, signalling in cells, right through to clinicians that work with patients. It's not all in one building, but the one institute covers many areas.
Is that a good approach?
Yes, it's changed the overall culture – the way we think about what we do – to bring more targeted impacts; the kind of thing funded by BBSRC and informed by our interest in ageing.
- Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms