An improved brace of sulfations

After preprinting our two papers (here and here) on inhibitors of sulfotransferases they were submitted to Biochem J. The referees made some excellent suggestions – a bit of work, but the extra controls add even more certainty, which is never a bad thing.

The papers are published back to back.  The Biochemical Journal recognised the fundamental importance of the papers in opening up a new area of signalling  with an accompanying editorial by Sharon Yeoh and Richard Bayliss, as well as the issue cover.

Our papers describe the first high throughput assays for sulfotransferases, the enzymes that transfer sulfate from PAPS to their substrates. These assays were developed in parallel for three Golgi sulfotransferases; the two tyrosyl protein sulfotransferases, which sulfate selected tyrosines on proteins, and heparan sulfate sulfotransferase 2, one of the polysaccharide sulfotransferases responsible for the sulfation of heparanosan, and so producing the protein binding sites in the heparan sulfate product. Heparan sulfate has long been known to be associated with Alzheimer’s Disease

More recently, heparan sulfate with an unusual sulfation pattern has been shown to accumulate in neurons in experimental models of Alzheimer’s Disease and so to drive the formation of Tau fibrils, which is integral to the Taupathy seen in Alzheimer’s disease. The development of screens for inhibitors of thee enzymes described in our two papers also demonstrates that PAPS competitors can inhibit sulfotransferases selectively. At the very least this will allow a chemical biology approach essential to elucidate the relationship between heparan sulfate and Tau fibrillation in cells and so establish the structure-function underpinnings of a longstanding molecular pathology of Alzheimer’s Disease.

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ArrestAD meeting La Rochelle

Our first results-driven scientific meeting was held in La Rochelle, France, on October 6 and 7. In addition to the research teams, we also had our two external advisors. It is important to have outside views on research and their substantial contributions were very much appreciated.

The UPEC group did a fantastic job in organising and structuring the meeting.  There was plenty of formal time for discussion, as well as time for informal discussions around the breaks, meal times and evening. The meeting itself covered the entire range of topics that lie within the ArrestAD programme. Talks included a recap of our objectives and strategy, administrative matters, ethics, and communication plans. The latter have an important ethical angle, as institutional publicity offices often oversell research. In the case of biomedical research, and perhaps very particularly to neurodegenerative diseases such as Alzheimer’s, over positive spinning of research results would likely be upsetting for patients and families. So this is something we will avoid. On the research front, substantial progress has been made on all fronts, from the patient side (patient recruitment, sample processing and so on) to the molecular and research tools. The good news is we are well up on our deliverables and hitting the milestones in each WP and as at our Kick Off meeting, we all learned a lot from each other.

The group as a whole, though we have not met often, gels very well. The extensive discussion time allowed forward research planning between teams, something that always takes time in multidisciplinary research.

The trip to La Rochelle also enabled a number of us, on the way in or the way out, to visit UPEC, where our Coordinator works. This was to ensure that we could plan in detail those parts of the research that will involve two labs working together on a particular task. In our case, this was to determine how we will extract the heparin-binding proteins using Liverpool protocols on French patient samples in UPEC. Happily, all is in order and we should move smoothly onto this phase of the work mid- to late 2018.

Our next meeting, which will be the PIs only, will be in Brussels in February 2018, when we present our progress to the external panel appointed by the European Commission. This will provide excellent feedback, as well as a chance for the team to discuss their progress.ArrestAD La Rochelle Group picture

Consortium Agreement Signed

ArrestAD started on January 1, and our Kick-Off meeting was on Jan 5, but there remained one important task to complete before the project was actually  up and running: for all participants to sign the Consortium Agreement. This documents was signed by all partners, and provides a framework to manage the collective work of the participants. For many of us, we have one more hurdle – finding good postdoctoral researchers (see “job offer”). These are scientists who have complete a PhD, after which they will generally undertake 2-9 years postdoctoral research. This combines high calibre research with further training and development of their scientific skills, which allows entry into industry or public sector research organisations as a research leader.