Previous work in this laboratory has shown that children with autism usually have very low levels of plasma sulphate, with high excretion of sulphate ions in urine. This leads to a number of problems, as sulphation is essential to so many biochemical processes. In particular, it is required for the inactivation of neurotransmitter amines such as dopamine and is vital in the digestive process. The cascade of enzymes that finally results in the release of digestive enzymes from the pancreas needs sulphation of the gastric hormone peptides gastrin and cholecystokinin for this process to take place, while mucins, the proteins which line the digestive tract, are also sulphated. If this process is blocked for some reason, then the gut becomes leaky and peptides, rather than the amino acids themselves cross the mucin barrier into the blood stream where they can affect brain function or cause food intolerance.
Cytokines and Sulphation
Report on scholarship awarded to Ms Lucy Wilkinson, School of Biosciences, University of Birmingham by Autism Unravelled
Against this background, we decided to study factors that could be responsible for the low levels of sulphate. Normally, most of the sulphate in the body comes from the oxidation of the amino acid cysteine; the initial and rate-determining step in this process is controlled by the enzyme cysteine dioxygenase, CDO. This enzyme is very unstable and difficult to study and is found in liver and in brain, with smaller amounts in the kidney, lung and thyroid. Lucy grew human liver and brain cells in culture and then dosed them with cytokines. These are small proteins that are involved in the inflammatory process. One of the most important is TNF-alpha, which is released after infections. For reasons that are not understood, TNF-alpha levels are high in children with autism and remain high even when the original infection has cleared.
Lucy's work showed that TNF-alpha, at the sort of levels that would easily be reached in an infection, blocked the formation of the CDO enzyme. She used all the modern techniques of molecular biology to show this result, which does explain why autistic children could have low sulphate levels. She has also gone on to look at other cytokines. Some block CDO expression, just TNF-alpha, but we have found two cytokines which appear to activate CDO formation. Obviously, this would be useful therapeutically and we are now trying to find out how these activating cytokines actually work. When we have done this, we hope that we will be able to offer a way of improving sulphate production in autism. Thanks to help from Autism Unravelled, the University of Birmingham Business Development Unit has now agreed to help us take this project further as we are aiming to produce peptides that would activate CDO formation. These would be relatively cheap, unlike cytokines, and could be designed to avoid side effects. In the long term, they could be a very useful treatment.
Dr Rosemary Waring PHD, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT
Phone: 0121 414 5421 Fax: 0121 414 3982 Email: r.h.waring@bham.ac.uk
Article by kind permission of Autism Unravelled.
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