The role of UBE3A in flies is the same as in humans

The Angelman Syndrome Association (ASA) Spain organised a seminar last September, where PhD Ugo Mayor explained the line of research that is being conducted in his laboratory on Angelman Syndrome. He has recently released his discoveries to the scientific community and it is for that reason that ASA aimed to interview him in order to find out all about his discoveries and progress.


Why did you decide to start research on Angelman Syndrome?

I have been doing research in the functions of ubiquitin since 2004, with a special interest on the regulation of the brain. At the time, most labs working in the ubiquitin field were focused on developing strategies that work mainly in vitro, but which can not be used to which we applied first to fruit -flies- that can be used to characterize ubiquitination in vivo. After considering a number of relevant pathways we could aim to characterize with our technique, I realized that research on AS should be our priority, as it represents a paradigm of the importance of ubiquitination in neuronal development and function.

We know that AS is an alteration of chromosome 15. What is actually its cause?

From the two copies of the gene for the ubiquitin ligase UBE3A we all have in our cells, only one is usually activated in our brains. If there is for some reason a problem in this region of the chromosome 15 where UBE3A is located, and this copy of UBE3A is not activated, our brain would lack the ubiquitin ligase activity of UBE3A. While UBE3A is just one out of over 500 ligases humans have, the lack of its activity results in AS. Most ubiquitin ligases are capable of attaching ubiquitin to more than one substrate or client proteins. A signicant amount of research is ongoing to map which substrates do each ubiquitin ligase target, but in most cases we do not yet know them. This is still the case for the substrates of UBE3A, despite some results exist pointing to likely substrates.

What is ubiquitin and what function does this protein have?

sort of way to regulate at the required time and location most other proteins within cells. A protein tagged with several ubiquitin molecules can for example be targeted for degradation, but depending on ubiquitin is attached, it might instead be directed to interact with a third protein, or sent to a different location within the cell. The ubiquitin code is still not fully understood, but we know now much more than 30 years ago, when research on ubiquitin just revealed the importance of this small protein. Such work was recognized by a Nobel Prize 10 years ago.

We have recently read you just published some advances in your research. What have you found?

Using a model system we have identied and validated some UBE3A substrates that could explain a number of observations reported before for Angelman Syndrome. The UBE3A gene is not only present in humans, but also for example in fruit -ies, a simple organism used for research because of its versatility. The role of UBE3A in -ies is exactly the same as in humans, and -ies lacking it also display a failure of neuronal functions that mirrors –within their own scale of capabilities- the syndrome that develops in humans.

What do these developments imply for AS research?

While so far our results are only based on one model system, and therefore will need to be validated in higher organisms, as well as in human samples, we have observed that UBE3A regulates the proteasome. This confers a higher level of complexity to the molecular network controlled by UBE3A, as the proteasome is a central regulator of protein degradation. However, our results might actually offer an explanation to the regulation of other proteins that had been described as UBE3A substrates before, but which were actually never conrmed to be ubiquitinated by UBE3A.

And now what? What is the next step you are planning for your research?

Once we have conrmed that our strategy can be used in -ies, we are now expanding our research into mice, a model organism much closer to us, and which will hopefully help us understand better how AS develops. Additionally, and in collaboration with Dr Reiter in Memphis, we are aiming to validate our results in dental pulp derived neurons from patients.

Where do you obtain funding for your research?

When I arrived to the CIC bioGUNE, a research centre near Bilbao (northern Spain), I was given some generous support by the centre to set up the lab. Later I obtained a March of Dimes grant that has funded our research on AS during the last 2 years. This year, we have been fortunate to receive a direct economic contribution by the Asociación Sindrome de to support our research for the year 2014. This has been an essential support at a time we are waiting for the resolution of a grant application to the Spanish main source of support for research.

Last, a question we all ask ourselves. Will we ever see a cure for AS?

That is the trickiest of all the questions so far. Obviously, I would like to say “Yes, no doubt”. But, at the same time, I think it is essential that we do not create false expectations. In contrast to not so long ago, we now understand what gives rise to AS. However, we don’t know yet what goes wrong at the molecular level as a consequence. Depending on what exactly is happening, it might be more or less likely that finding a therapy for AS compensating for the neurological manifestations might be achieved within a reasonable time. Science is advancing fast, so the chances to nd a cure for AS are obviously increasing every day. And surely research on AS will continue until a cure is found. Until then, life has to continue, and making the best of the given circumstances is probably the best present a child with AS will receive.


More information:

Who is Dr. Ugo Mayor?

Born in San Sebastian (Basque Country, Spain), Ugo Mayor finished his studies in Lund Universitet (Sweden), and then went to the University of Cambridge (UK), to work on ultra-fast folding proteins under the supervision of Prof. Sir Alan R. Fersht. His PhD thesis resulted in several landmark papers. In 2004, Dr Mayor was granted a Dorothy Hodgkin Fellowship from the Royal Society (UK). Moving into the lab of Prof. Andrea H. Brand at the Gurdon Institute involved a significant change in disciplines, aimed at bridging the gap between protein biophysics and developmental neurobiology. Using a novel approach to isolate ubiquitinated proteins, Dr Mayor was able to describe the ubiquitin landscape in the embryonic brain during development. He received in 2012 a Basil O´Connor Starter Scholar Research Award from the March of Dimes, and focused his efforts in identifying the substrates of the UBE3A ubiquitin ligase, whose failure causes Angelman Syndrome. Dr Mayor is based at the CIC bioGUNE research centre (near Bilbao, Spain) with an Ikerbasque Researcher position.