Professor Robin Williams

Robin Williams

Professor Robin Williams

Head of Centre, Professor of Molecular Cell Biology

Phone: +44 1784 276162

Research interests

Interested in bipolar disorder research - then please visit

Bipolar disorder: molecular and cellular biology
Royal Holloway, London, UK April 2009

Overview of current research

Epilim, Epival, Orlept, Divalproex, Depakote, Valproate and Valproic acid (VPA) are different names for the same medicine - a short chain fatty acid (2 propyl pentanoic acid) - that was accidentally found to have intrinsic anti-seizure properties in 1963, and is now a mainstay in epilepsy treatment. However, its therapeutic roles have broadened, as it is now one of the first-used treatments for bipolar disorder (manic depression), it is used in migraine prophylaxis and it is under trial for cancer, HIV and Alzheimer's disease treatment. It also has two serious side-effects: teratogenicity (causing an increased chance of embryonic malformations) and hepatotoxicity. Despite the wide use of VPA, and considerable research into its therapeutic targets, how the drug functions in these roles remains unclear.

Understanding the therapeutic mechanism of action for valproic acid (VPA) has been complicated by a number of different cellular effects of the drug. In regards to bipolar disorder treatment, scientists have often looked for common effects of VPA and another bipolar disorder treatment, Lithium (Li+).

Investigations into the function of VPA, using diverse models from simple eukaryotes such as the social amoeba Dictyostelium to primary mammalian neuronal cells, has led to the identification of a variety of signalling pathways targeted by the drug. These include the modulation of inositol trisphosphate (InsP3) signalling, activation of the MAPK signalling pathway, and reduction glycogen synthase kinase (GSK3) activity. VPA also chronically attenuates arachidonic acid release, interrupts GABA signalling and modulates phospholipid signalling and sodium channel activity. Significantly, for many of these targets, the actions of VPA are indirect via an unknown mechanism, may be linked or independent of one another, or may be related to therapeutic or adverse effects. The multiple effects of VPA, and the ability to test for these effects using VPA-like compounds with slight changes in chemical structural, also enables us to associate distinct chemical structures with different targets.

Dictyostelium is a simple eukaryotic, increasingly being used as a model for understanding biomedical problems. (a) Dictyostelium's unusual life cycle, involving both single and multi-cellular stages provides an advantage for understanding the molecular cell biology of some biomedical compounds. (b) The mature fruiting body take around 24 hours to develop, comprises up to 100 000 cells, and is approximately 1 mm in height (bar = 0.1 mm). Reprinted from Trends in Molecular Medicine, 12, Williams et al., Towards a molecular understanding of human diseases using Dictyostelium discoideum, 415-24, Copyright (2006), with permission from Elsevier.

Our research aims to understand and separate the numerous molecular effects of VPA, using the simple biomedical model Dictyostelium, and mammalian cell systems. This work will ultimately allow us to understand the origins of epilepsy, bipolar disorder and migraine, and the processes involved in these conditions leading to ill health. We further aim to identify novel compounds for treating these conditions with potentially stronger therapeutic effects or reduced side-effects.

Research group
 
  • Dr Nadine Pawolleck (Postdoctoral Fellow)
  • Ms Nicole Terbach (PhD student)
  • Ms Nichol Pakes (PhD student)
  • Ms Marthe Ludtmann (PhD student)
  • Mr Ben Orabi (MPhil student)
  • Mr Manik Dham (Masters student)

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